Augie March is a Jewish-American boy growing up fatherless and poor in Depression-era Chicago. He seeks a "special destiny", although his circumstances seem to position him for a uniquely disappointing life: his family consists of a simple-minded mother, a brother and "grandmother" who prove to be Machiavellian in their intentions, and an "idiot" youngest brother, Georgie.
In the absence of the father, Grandma Lausch offers Augie and his brother, Simon, lessons in how to survive and succeed. She teaches them first and foremost that respect is superior to love. After some time, Grandma Lausch suggests that the family place Georgie into a home for the impaired. The shock of losing Georgie, an embodiment of pure love, destabilizes the very foundation of the household. Grandma Lausch loses her tyrannical sway over the family, and, in an ironic twist, Simon contacts Grandma Lausch's real sons, who arrange to have her placed in an institution.
As a high school student, Augie works for a wealthy, "superior" man named Einhorn: a cripple with an excellent mind. He becomes something of a father-figure to Augie, and Augie eventually becomes more of a son to Einhorn than his real offspring, Arthur, who aspires to be a poet. In the Great Crash, Einhorn loses all of his property, but adapts to the loss with the vigorous spirit that characterized the times. Meanwhile, Augie successfully graduates from high school. As a graduation gift, Einhorn takes him to a brothel.
Augie takes courses at the city college, and eventually lands a sporting-goods sales job in the wealthy suburb of Evanston. He moves to the town, and a family called the Renlings take him under their wing. Mrs. Renling treats Augie like her own son, paying for his riding lessons and courses at Northwestern. She takes him along on a summer holiday, where he falls in love with the slender and pure Esther Fenchel. Esther, however, rejects him, even as her far more passionate older sister, Thea, professes her love. Thea leaves behind a note for Augie telling him that he will see her again one day, and that she truly does love him. Shortly afterwards, Augie and Mrs. Renling return to Evanston.
In Evanston, the Renlings make a formal offer of adoption; if he accepts, Augie will become "Augie Renling" and one day inherit all of their money. Augie refuses, infuriating Mrs. Renling, and returns to Chicago. He takes a miserable job selling paint, but before long he runs into Joe Gorman, who offers him a job transporting illegal immigrants into the country. Augie only agrees to help Joe drive the car out East, but on the way a police officer recognizes the car and arrests Joe, leaving Augie stranded. He evades the police, and returns to Chicago by jumping freight trains and hitchhiking.
Upon his return, Augie discovers that everything has changed. The house has been sold, along with all of the furniture inside. His mother, now fully blind, tells him that Grandma Lausch died while he was away. Mournful, Augie goes to see Einhorn, from whom he learns that Simon borrowed money to put into a betting pool. He needed to become a rich man in order to marry his girlfriend. In the end, however, Cissy Flexner married their wealthier cousin, Five Properties. Crazed and violent, Simon spent a night in jail, and has now gone into hiding. When Simon reemerges from his shameful, self-imposed exile, Augie finds him fatter and less healthy-looking. Simon declares that he plans to marry into the wealthy Magnus family, and soon thereafter weds Charlotte Magnus.
Meanwhile, Augie runs into his Mexican friend Padilla, now a student of math and physics at the University of Chicago. Padilla gives Augie a job stealing books, and he settles into a room at a student house near the university, befriending a girl named Mimi Villars. Mimi becomes pregnant with her boyfriend Frazer's child, and Augie is the one who takes her to get an abortion. However, when the rumor about the abortion reaches the Magnus family, it destroys Augie's chances with Lucy, Charlotte's prettier younger cousin. Simon, enraged, states that he wants nothing more to do with his brother, and Augie is struck by the injustice of his situation. When Mimi recovers from her abortion and the infection caused by a previous surgery, she sets Augie up with a job as a union organizer. She also breaks off her relationship with Frazer and begins to date Einhorn's son, Arthur.
One night, while Augie is making love to a woman in his room, a knock sounds on the door. He recognizes the voice immediately as Thea Fenchel's, and answers the door. The two are reunited, and fall in love. Augie agrees to go with her to Mexico, where she plans to obtain an official divorce from her husband and train bald eagles to hunt for lizards. Augie begins to understand that Thea has a very extreme personality - fiery, yet honest - but loves her anyway. They travel to Mexico, settle in her family's house, and slowly set about training the young eagle they have adopted. Ultimately, however, the eagle proves to be a coward; he is afraid of hunting. Augie, feeling sorry for the creature, keeps trying to train him; but after falling on a rocky slope and seriously injuring himself, abandons the endeavor. Thea tearfully sends the eagle away to a zoo and nurses Augie back to health while beginning a collection of snakes.
Augie finds Thea's hunting obsessions disturbing, so one night when a beautiful woman named Stella begs Augie to help her escape to Mexico City, he infuriates Thea by agreeing to take her halfway. Augie insists that he only wants to help the girl, but he ends up sleeping with Stella. Stella kisses him in the morning and thanks him, suggesting that he visit her someday. Augie returns to Thea, ready to lie, but she has already intuited what has happened. She ends the relationship then and there, and leaves that very morning.
Augie, in mourning, returns to Chicago to find that Simon has become a wealthy man. They agree to forget their past troubles, and Augie learns that his older brother has fallen in love with Renee, his mistress. Augie then takes a job as a research assistant for a stingy millionaire named Robey, who is attempting to write a book on the history of human happiness. Augie also begins to teach at a local school. His break-up with Thea inspires him to become more introspective about what it is that he wants, and he confides in his friend Clem Tambow that there are "axial lines" in life that one must be able to live by. He reveals his dream of starting up a school, living with his mother and Georgie, marrying a good woman, and raising a family of his own. In other words, his vision is all about love. Clem, however, responds that Augie really wants to be "king".
The war begins, and Augie enlists. When he goes to New York to begin training, he decides to visit Stella. They fall in love and decide to marry. Through Stella, Augie befriends a man named Mintouchian, a divorce lawyer in New York, who provides him with worldly advice about adultery and love. Mintouchian himself is having an affair with Stella's friend.
Two days after the wedding, Augie ships out and begins spending all his time listening to tales and collecting stories. When his ship is torpedoed and sinks, Augie manages to survive along with one other man, a fellow Chicagoan and the ship's carpenter. This man, Basteshaw, reveals himself to be a mad genius who seeks to unlock the secrets of creating life. Basteshaw decides that they ought to float their way to the Canary Islands, where he can continue his mad experiments in peace, and he ties Augie up when he attempts to signal a passing ship for help. During the night, Augie frees himself and debates whether or not to throw Basteshaw overboard. In the end, however, he decides to let him live. Finally, a British tanker comes by and rescues them. Augie's suspicions about Basteshaw's madness are confirmed when he learns that they are nowhere near the Canary Islands.
After his rescue Augie returns to New York, and he and Stella move to Europe. In Paris, Stella finds work at an international film company. While Augie finishes his autobiography and manages Mintouchian's black-market dealings in Europe, Simon and Charlotte come for a visit. Augie asks Simon what happened to Renee, and learns that Renee had falsely claimed to be pregnant in an attempt to sue Simon for his money. In the end, the lawsuit disappeared, along with Renee, and Simon thinks that she is most likely married by now.
Augie senses Simon's disappointment about Charlotte's inability to bear children. Augie himself suppresses his own disappointment in his marriage to Stella, his rootless life, and his inability to secure a real profession. As he travels to Bruge with his housemaid Jacqueline, a ridiculous woman who tells him her dreams of traveling to Mexico, however, Augie finds that he can't help but laugh. The novel ends on this note of laughter, as Augie claims to be like Christopher Columbus: a man who has truly discovered what it is to be American.