The novel begins as the brothers Hermes and Apollo are having a disagreement. Hermes believes that there is something special and amusing about human behavior while Apollo believes humans to be no different than any other creature on earth. Each brother wagers a year of servitude to the other over a question central to their debate—would any animal, given human intelligence, "be even more unhappy than humans?" (14). They eventually decide that if even one of the animals dies happy, Hermes shall win the bet. Since they happen to be by a veterinary clinic when the wager is made, they select the fifteen dogs in the clinic as subjects and, leaving them with their memories, bestow human intelligence upon them.
The dogs each realize their new intelligence and decide to break from their cages in the clinic. They then invent a new language using their newfound faculties, different entirely from their simple and initial dog language. They escape the clinic, but three of the dogs choose to stay, ultimately dying for making this choice. The smells of the lake draw the other dogs in, but they eventually decide to seek shelter. Over time, their new language starts to deepen and grows more complex, particularly through the efforts of a dog named Prince, who invents words and puns. In thinking about time and place differently, they also construct a den in a coppice.
A schism occurs in the pack. While the dogs Max, Frick, Rosie, Frack, and Atticus (their leader, a Neapolitan Mastiff) wish to live as if they never had their sudden enlightenment—acting as they believe dogs should—other dogs like Bobbie, Bella, Athena, Prince, and Majnoun (a Poodle) believe that their newfound intelligence should be used. Majnoun and Atticus, the two most powerful dogs, discuss the future of their pack, and when Majnoun indicates that he thinks their intelligence should not be ignored, Atticus and company conspire to kill Majnoun and those aligned with him. At night, Frick picks up Athena in his jaws, kills her, and makes off with her. Frack then dupes Bella into trying to cross a road, where she is struck dead by a car. Prince, however, is spared by Hermes, who appears to Prince in a dream as a black dog with a blue patch on his chest. Hermes helps Prince escape invisibly using his godly power. Once Prince is far away from the others, he flees and begins his exile from the pack. Meanwhile, Atticus, Max, Frick, and Frack trick Majnoun and attack him brutally, leaving him for dead.
Majnoun later wakes up in a house after his attack, where a man and woman decide to keep him and name him Lord Jim. Six months later, Majnoun is recovering with the same humans and has been thinking constantly, both about his betrayal and about the nature of human communication. He is fascinated by the tones and inflections of the human voice, and he finds it interesting that they ask him questions as if waiting for a response. One day, the woman asks Majnoun whether or not he is hungry, and he speaks the words "yes" and "treat." This terrifies the woman, who flees the room, much to Majnoun's confusion. She takes him to a facility overnight where painful tests are conducted on Majnoun. The woman comes back for him on the third day of his internment. The woman introduces herself as Nira, and then reconciles with Majnoun, telling him that she was only scared because dogs do not usually speak to people. In turn, Majnoun refuses to speak to the woman and only nods to her.
Over time, Majnoun's silence and nods endear him immensely to Nira, whose husband is named Miguel. Nira talks to Majnoun about trivial things but eventually discusses matters like death and the divine with Majnoun. When Nira asks Majnoun if he has ever been in love, Majnoun cannot relate, only thinking of the loyalty he has for his master and the uncomplicated relationships of dominance he has with other dogs. By this point, Majnoun has been with Nira and Miguel for eight months, and he is already very close with Nira. His relationship with Miguel, however, is a bit odd—Miguel does not believe Nira about Majnoun's capacity to speak and thinks Majnoun's understanding of human language is perfectly average. On longer walks with Nira, people often ask to touch Majnoun, and he is picky about whom he allows to do so. He is also picky about where he chooses to walk, opting only to walk in High Park, where he was betrayed by his pack.
Eventually, Majnoun runs into Benjy, a self-interested and two-faced Beagle with impeccable instincts. Majnoun helps Benjy ward off another dog, and then asks what has happened with the pack, although to no avail. Benjy performs typical tricks for Nira, and she offers to take him home with them. Majnoun is somewhat annoyed, but Benjy is excited for the opportunity to learn English from Majnoun. Benjy offers to tell Majnoun about the pack in exchange for instruction in the English language. At Nira’s house, Majnoun insists on knowing what happened to the pack. Benjy then begins telling his account of what happened with the pack, but he leaves out any details that might incriminate himself.
Benjy was awake for the killing of Athena and when he inferred that Bella was also being killed and recognized who the conspirators were, he fled from the coppice in the commotion surrounding Prince's disappearance. After witnessing the supposed killing of Majnoun and seeing his "dead" body, Benjy returned warily to the coppice, not recognizing any pattern in who was killed by the conspirators.
The next morning, Bobbie and Dougie (a Schnauzer) asked after the other dogs, and Atticus explained that he was in charge. Atticus then banned the new language in favor of a return to acting like normal dogs. Bobbie objected and chose exile, but the conspirators immediately attacked and killed her. Benjy says that the days which followed were strange—both because Benjy and Dougie were now the obvious pack submissives and because Atticus insisted that they act like true dogs, even if this meant acting in a way that one could no longer really remember accurately. Eventually, the conspirators and larger dogs let Dougie and Benjy go out by themselves in search of food and materials, which led Dougie and Benjy to become friends.
One January morning, Benjy and Dougie set out from the coppice. They realized that the larger dogs no longer treat them as well as they used to, so they decided to flee. They eventually ran into an old woman, who took them in and treated them well. Eventually, Dougie decided that he could not live in her home anymore and killed one of the old woman's other pets, a haughty cat. When he left it near her bed, the old woman came downstairs clearly in shock and displeased. To release the tense emotions they felt within, Benjy and Dougie then began to burst out in laughter. This made the old woman open the door, before falling to her knees and praying. Seizing the opportunity, Dougie and Benjy fled and returned to the coppice, with Benjy following some distance behind Dougie. Benjy then saw Dougie run straight from the den upon returning, pursued by the others who intended to kill him. Benjy then told of Dougie's subsequent mauling and death. Though he thought for sure that he too would be killed, Benjy was spared but forced to stay in the den even though he no longer belonged there.
One afternoon, Rosie suddenly addressed Benjy in the forbidden tongue and told him that he should not try to run away. When he asked why they would hurt one who seeks to flee, Rosie told Benjy what happened to Max, who was murdered after he resisted being mounted. This story made Benjy realize that he, as the bottom of the social totem pole, was just as important to the pack as Atticus. After two months, Benjy found a "garden of death" poisoned with toxins to keep out dogs, pests, and other animals. He then resolved immediately to kill the others in the pack by seeking out the garden and having them eat there. The next day, Benjy drew them to the smells of the garden and gently nudged them in its direction. They all ate heartily of the food except Benjy. Eventually, all other dogs besides Benjy died from the poison.
As Benjy's account concludes, Majnoun thinks to himself that he mistrusts Benjy; nonetheless, he has a sense of fraternity with him because they are of the same pack.
Majnoun begins to teach Benjy English, forbidding him from talking to Nira. Even so, Benjy eventually goes around Majnoun to do so for practice and asks Nira for things like food and water. When he asks Nira for money, however, she spurns him and tells Majnoun. Majnoun bites Benjy and warns him, but Benjy does not see this as a real threat. Benjy instead starts speaking English to Miguel, who takes this for a trick by Nira. When Nira says that Jim (Majnoun) must have taught Benjy how to talk, he is upset with what he takes to be her coyness and teaches Benjy the opening lines of one Nira's favorite novels, Vanity Fair. He hopes to surprise Nira by having Benjy recite these words. That never happens, however, due to the changed dynamic in the house. Nira has developed a mistrust of Benjy, while Miguel has developed palpable scorn for Majnoun. Majnoun notices that Benjy is angling for status, correcting Majnoun's pronunciation during their lessons and sniffing Majnoun's food before eating his own. In response, one day when Nira opens the door for the two dogs, Majnoun attacks Benjy and attempts to kill him, driving him out through a gap in the fence. When Nira comes outside, Majnoun only says that Benjy ran away, and they never speak of the dog again.
The narrative then flashes to Mount Olympus, where a stir has been caused by the wager between Apollo and Hermes. The other gods are interested in the contest between the two and make their own bets, but Zeus is furious upon discovering what Apollo and Hermes have done. He forbids them from interfering any further with the dogs' lives, and he tells his sons that they are "worse than humans" in their cruelty toward the dogs (92). Though he has forbidden his sons from intervening in the dogs' lives, Zeus himself then chooses to intervene on behalf of his favorite dog, Atticus.
The catastrophe resulting from the deaths/disappearances of Max, Dougie, Benjy, and Bobbie then lead Atticus to begin praying. Perhaps spurred by his own feelings of inadequacy as a leader, Atticus begins to imagine an ideal dog with all the noble qualities of leadership he believes in, and he thinks that such a dog must exist because, were it not to exist, it could not be an ideal dog. With this newfound faith, Atticus begins leaving offerings and praying. Zeus takes notice of Atticus and appears to him in a dream. Zeus tells Atticus that, upon his death, he will grant him one wish. We are then shown the events that were previously relayed by Benjy—the killing of Max, the killing of Dougie, and the poisoning—throughout which, we are told that Atticus kept his faith. When Atticus started to realize that something was wrong after being poisoned, then, his dying wish was that "the one responsible for his pack's demise be punished" (98).
Our perspective then shifts to Benjy just after he fled Majnoun's attack in Nira's backyard. While he still maintains hope that Majnoun will calm down and allow him back into Nira's home, he first begins to wander around and thinks about where to go to kill time and stay safe. An old man appears and offers him a biscuit, and then addresses Benjy by name and says he needs to go. Intrigued by the man's use of his secret name, Benjy follows the old man onto a streetcar. The man is really Zeus in mortal guise, and he disappears from the streetcar while Benjy is distracted by the scents and sights out the window. Benjy is eventually noticed by the driver of the streetcar, so he flees out the doors and heads towards the beach on the lake. Suddenly, a mutt appears and happily pounces on Benjy. It is Prince, who tells Benjy that he has been a number of places since his ousting. While Prince is ecstatic to speak his language with Benjy, Benjy insists that only the human language is important, and that he shall teach him if he likes.
Benjy tells Prince that he and Prince are the last of the pack. Despondent at this news, Prince then tells Benjy about what has happened to him since he fled the pack. Prince says that, after fleeing, he stayed with a variety of masters whom he always fled or ran away from on accident. Benjy asks Prince if he has a current den where they might get some food, and Prince takes Benjy to a home near Rhodes and Gerrard. Eventually, a man comes out and calls his partner Clare, saying that her friend has brought another dog with it. Sensing an opportunity, Benjy recites a bastardized version of the opening of Vanity Fair that he had earlier memorized. This draws the attention of the two owners, who take him in. Prince, however, is ousted and never sees Benjy again.
The man's name is Randy, which Benjy learns easily. He thinks that Clare and Randy's life up close is interesting in some regards and unexceptional in others. The one thing that confuses Benjy is seeing Clare penetrate Randy in the bedroom while Randy wears a black leather suit and is beaten by Clare. This makes Benjy wonder about whether the true leader of the house is Clare or Randy—who, in being rash, violent, and intimidating, would otherwise be the clear leader. The power vacuum that Benjy sees in the house leads him to assume his own dominance and think that he can manipulate Clare and Randy. Meanwhile, Clare and Randy are each growing quietly contemptuous of Benjy. Benjy spends six months with Clare and Randy and is mostly left to his own devices in this time. When Randy loses his job, however, they skip their rent and flee to Syracuse, leaving Benjy behind. They tried to get Benjy to come with them, but Benjy's dominant mindset made him ignore them. Benjy begins to starve, and the smell of rat traps in the cupboard attracts him. He eats all of the poisoned pellets and dies an exceptionally painful death. As he dies, however, he hopes for a world to come where the social hierarchy is clear and rigid, and this thought makes him happy, even to the point where we are told that Benjy dies "into hope itself" (117). This then leads to another disagreement between Apollo and Hermes over the nature of hope.
While all this transpires, Nira and Majnoun grow closer and more intimate, though they have minor disagreements about Majnoun’s typical canine behavior (e.g., eating feces, mounting female dogs). Later, the two have a disagreement over whether Miguel is the pack leader of their household. Majnoun growls and threatens Nira as a display of the equality he perceives them to have, which creates distance between them. Since Majnoun would ultimately never hurt Nira, however, he decides to flee the house one day. Seeing Majnoun flee, Hermes is upset: he believes that, if Majnoun were to continue living with Nira, he could die a happy death. Hermes decides to illegally intervene once more in his wager with his brother. He appears to Majnoun in a dream, telling Majnoun that his future is with Nira and that he will no longer misunderstand the intention behind her words. When Majnoun wakes up, he has been gifted the ability to speak and understand all human languages, which allows him to connect with Nira in unprecedented ways. He composes English poems for Nira and tries to teach her dog language. Eventually, Nira even stops thinking of Majnoun as a dog.
Two years pass. Majnoun begins to appreciate Nira in a different way—that is, by watching her favorite movies and consuming other media with her. In the process, Majnoun meditates on his sexuality and grows fascinated by the way human art eludes understanding. At the same time, there is a complementary struggle to acquaint Nira with dog culture because of its lack of relics and artifacts. When he tells her a dog story about conflicting desires with no clear ending, for example, Nira struggles to understand and fully grasp it.
The distance between Nira and Majnoun continues to narrow. One night, they even have a shared dream of looking into a pond and seeing the reflection of the other. After this, Nira refuses to address Majnoun as her dog, saying "I'm as much his as he's mine" (132). This, unfortunately, is a portent of ill fortune. Majnoun's preordained time to die has come, but the Fates are unsure of how to kill him off since Majnoun's thread has grown so close to Nira’s and Miguel's. Their three lives are bound inextricably together in a way that cues the Fates to think that a god has interfered in the mortals' lives. Atropos complains to Zeus, who is unsympathetic to her pleas; as a result, Atropos cuts two of the threads at random and adds life to the remaining thread.
Our perspective then switches back to the household of Nira and Miguel. They are arguing over housework, but in reality Miguel is jealous of Nira being able to stay home all day and work while he must leave to go to work. Majnoun thinks that Nira and Miguel need time alone, apart from Majnoun. Miguel and Nira plan to go to some wineries and spend a few days on vacation, and they will leave Majnoun alone for the weekend. After the weekend ends, however, Majnoun notices that Nira and Miguel have still not returned. We are told that the dog's heightened consciousness of time due to his new intelligence in particular makes this painful for Majnoun. Eventually, strange people appear and wonder who Majnoun is. They are Miguel's brothers and mother, and they seem to be discussing who might take Majnoun and what to do with the things in the house, which they rummage through. Majnoun realizes that Miguel's family is not loyal to him and wants nothing to do with him, so he leaves and returns to the den in the coppice.
The next day, Majnoun begins a vigil that will last years, returning to a spot near Nira and Miguel's house and waiting for her to return, since he has not fully grasped the fact of her death. Majnoun waits every day for Nira, scrounging in the park and taking food left outdoors at a dog cafe. Eventually, however, the nature of Majnoun's waiting changes. When a "For Sale" sign appears at Miguel and Nira's home, interest in Majnoun dies down as a new family moves in. He frequently switches vantage points and takes food from the neighbors, who understand that he is waiting and do not take him in nor turn him in to Animal Control. Throughout his vigil, Majnoun thinks about two things more than anything. First, he thinks about what it might mean to be human, and what changes in sensory perception are attendant to being human. Second, he wonders about what it is that makes him a dog.
Five years into Majnoun's waiting, Zeus takes notice that his life is unnaturally long and that he is miserable. Zeus goes to the Fates, but they are callous with him because of his earlier indifference. They agree that if Zeus is able to convince Majnoun to give up his vigil, then they shall release him into the next life. Zeus then goes to Hermes and Apollo, who argue about who shall help Majnoun. Hermes is chosen, but both acknowledge that Majnoun will be unable to die happy without Nira. Hermes realizes that, by giving Nira and Majnoun divine intimacy, he has made his own task much more difficult. Nonetheless, he appears next to Majnoun one day and speaks to him in both dog language and English. Majnoun recognizes Hermes and asks to be taken to Nira, but Hermes says he will have to leave this place to do so. Majnoun is unprepared to do this, however, so Hermes simply waits and keeps him company. Majnoun asks Hermes what it is like to be a god, and Hermes replies that he cannot express this in any language and that his manner of feeling is totally different. Majnoun wants to ask Hermes many questions about philosophy and life, but the only important thing to him anymore is Nira's whereabouts. He does not ask, however, for fear of the answer, and Hermes in turn does not press Majnoun.
Eventually, Hermes says he knows that Majnoun wants to ask him a question. Majnoun asks Hermes the definition of love. Hermes tells Majnoun that love does not mean one thing and never will; moreover, he tells Majnoun that when Nira said it, she meant something conditioned by the long journey of her own life experiences. Hermes takes Majnoun on a long metaphysical journey, showing him each point at which Nira's definition of love was formed. This deep understanding of Nira's being makes Majnoun crave her presence, and the pain of her absence is so unbearable that he agrees to give up his vigil and join her in the afterlife. As the chapter closes, Hermes (as a psychopomp) guides Majnoun's soul to the afterlife.
Our attention then turns to Prince—specifically, a description of his early life. Whelped in Ralston, Alberta, Prince is a mutt born to mutts, and he is taken in by a kind family with a son named Kim. Kim and Prince grow incredibly close, but eventually Kim gets in a fight with his parents and runs away, taking Prince with him. They travel to Toronto together, a place totally unfamiliar to Prince, and Prince loses Kim one day while chasing after a particularly enticing and irreverent squirrel. Eventually, Prince wanders and is ultimately taken in by the people who leave him at the veterinary clinic at King and Shaw.
We then turn to the moment of Prince's enlightenment, and the narrator tells us that the transformation affected Prince differently from all of the other dogs: namely, Prince in particular began to think of language and naming as fascinating. We are told that because of the strange and bewitching effect of Prince's language—which is, in large part, owed to his recitation skills—he gained a new form of status that scared the conspirators, leading to his eventual ousting from the pack. Throughout it all, however, Prince remained fascinated with his pack's language.
Apollo notices Prince's overflowing love for his pack's language and, as the god of poetry, he is upset that another poet's passion may cost him his wager with his brother. He and Hermes then begin to argue about whether the language of their bet is, in focusing on the moment of death, precise enough. Though Apollo is worried about losing and tries to get Hermes to give up the bet, Hermes is unrelenting. As a result, Apollo decides that he will violate Zeus' edict and involve himself in Prince's life, making the now fifteen-year-old dog suffer.
Our attention then turns to Prince in the narrative present. While he has had plenty of time to explore the city over his many years, he has a special place in his heart for the beach. This is all taken away, however, when Apollo sends poisoned sand into Prince's eyes and makes him blind. Once he goes blind, Prince realizes that, despite finding humans overly emotional, threatening, and distracting, he will have to take shelter with one for the rest of his days.
Making his way out from the park, Prince is struck by the persistence of fascinating smells and aromas, but he falls down stairs twice and hurts himself. His task of getting to his new home, however, motivates him to get up and keep going. He is able to navigate certain areas and forests almost perfectly—being part of his well-trodden territory—but crossing the street proves particularly dangerous and nerve-wracking for Prince. He sleeps in some gardens and wakes the next morning shivering from the cold. He is still dead set on getting to his new home, so much so that he only stops by the lake to take the scent in before continuing up the boardwalk to his new home, a place on Neville Park.
The family who lives there takes Prince in and treats him well, but Prince still mourns the loss of his faculties. Though he feels he has triumphed over blindness, he is mournful that, when he dies, so too will the language of his pack and his poetry. In an effort to preserve it, Prince recites one of his poems for the mistress of the house whenever he senses that she is near. Eventually, she senses that Prince is trying to say something, and she repeats it back to him. Prince feels that this is yet another breakthrough, but Apollo will not let Prince be happy and renders him deaf. After this final loss, Prince retreats inwardly and stops eating and drinking, waiting for death. His mistress takes him by the lake one last time, which he smells and finds relaxing, but he is then taken to be put down at a clinic. As he lies awaiting death on the table though, one of Prince's own poems returns to him as if someone else is reciting it and this gives him joy. He dies happily with this feeling.
Later, Apollo and Hermes discuss the aftermath of their wager and plan possible future bets regarding humans and their intelligence. Hermes leaves the tavern and gets into a cab. Though he knows that he is infinitely more knowledgeable and powerful than the driver of the cab, he still feels a divide between them. This is the divide of mortality, which separates absolute power and knowledge from love and fragility. Hermes wishes to know how the mortals live and feel. Finally, Hermes' thoughts center on Prince and his fears about his poetry being forgotten. We are told that, for the immortals, poetry always exists in the present and is never forgotten. Thankful for Prince's poetry and feeling magnanimous, Hermes then gives Prince one more gift. In Prince's final moments, he imagines himself to be in a field in Ralston all over again. He hears the voice of Kim calling him from across the field, understands it fully and perfectly, and starts to bound towards Kim. As the book closes, we are told that, "in his final moment on earth, Prince loved and knew that he was loved in return" (171).