The novel begins with the narrator's description of the curse, called fukú americanus—a curse of doom, specifically that of the New World. It was brought over to the islands of Antilles when the Europeans came, and has stayed ever since. The narrator makes the claim that the late dictator, Rafael Leónidas Trujillo Molina, has a close connection with fukú. The narrator informs the reader that he will be telling us the story of Oscar de León, who was the victim of his family’s fukú. The only known way to counteract a fukú is to use the term “zafa” to ward off the curse. The narrator then wonders if writing this book is his way of saying a zafa.
The first chapter, which takes place in 1974 – 1987 in Paterson, New Jersey, details Oscar’s childhood and adolescence. For one week when Oscar is seven, he dates two girls, Maritza and Olga, at the same time. However, the threesome soon falls apart and Oscar’s life goes downhill from then on. In adolescence, he is fat, dorky, and unattractive. Oscar’s interest in Genre makes him even more undesirable, and his only friends are Al and Miggs. Oscar’s tío Rudolfo and Oscar’s sister Lola both try to encourage Oscar to lose weight and be more masculine so that he can land a girlfriend or a lay, but Oscar does not heed their advice. When Al and Miggs find girlfriends and purposely leave him out Oscar realizes that even they think that he is a loser. Oscar goes and visits his Nena Inca in Santo Domingo, and turns to writing science fiction as an outlet.
When Oscar returns he meets a girl named Ana Obregón at his SAT prep class and falls in love with her. Ana and Oscar become good friends, but are never physically intimate. Eventually Ana’s boyfriend Manny returns from the army and Ana stops spending time with Oscar. Soon after, Oscar goes to college at Rutgers. Oscar hopes life in college will be different, but while there, he realizes that he is still a loser.
The second chapter takes place in the years 1982-1985. It starts in Paterson, New Jersey. Lola narrates in the first person. She describes the day that Belicia (her mother) calls her into the bathroom to help her examine a lump that she has found in one of her large breasts. Lola gets a bruja, or witch, feeling that something is about to change. After Belicia is diagnosed with cancer, Lola feels she has less power over her. At fourteen, Lola cuts all of her hair off in an act of defiance against her mother. A major turning point in their relationship occurs when Lola slaps away Belicia’s hand when she is about to hit her. Soon after, Lola runs away to live with a boy named Aldo on the shore in Wildwood, New Jersey. Lola loses her virginity to Aldo. Their relationship is rocky, and Aldo’s father is not much better to live with than Lola’s mother was. Lola gets lonely and calls Oscar. She asks him to meet her at a coffee shop on the boardwalk. When Oscar shows up, he brings their aunt and uncle and their mother. Lola then must live in Santo Domingo with her Nena Inca. There Lola attends high school, joining the track team and making friends. She also dates a boy named Max Sánchez. Lola’s bruja feeling comes back, and she realizes that the relief from the feeling comes from the stories that La Inca tells her about her family's past.
The third chapter takes place in Santo Domingo in 1955-1962, when Belicia lives with La Inca and comes of age. The narrator starts the story right after Beli moves in with La Inca. He notes that before this Belicia lived an awful life with an adoptive family that mistreated her. Beli attends the private elite school El Redentor, but she makes no friends and invokes fear in others because of her volatile attitude, a toughness she adopted from her rough upbringing.
When Beli hits puberty, she develops large attractive breasts and men start to express their desire for her. Beli then pursues her long time crush, Jack Pujols, who is the most handsome boy at school. Soon they are having sex in the broom closet. While Beli thinks that Pujols loves her and wants to marry her, in reality Pujols is already promised to a wealthy girl. When they are caught, Pujols is punished and sent away to the army. Beli is heartbroken. Beli then gets a job as a waitress at a Chinese restaurant called Palacio Peking. Belicia attracts two suitors during this time, but does not sleep with either of them. Then Belicia meets the Gangster, an older man who has a direct affiliation with Trujillo. Beli falls in love and ends up pregnant with the Gangster’s child. The Gangster is married to Trujillo’s sister, who takes revenge on Beli by having her beaten and causing her to miscarry. She is left for dead in a cane field, but a Mongoose with lion eyes appears and leads her out of the field. Beli then leaves the country to live in New York City, and on the plane ride there, she meets the man who will become Oscar and Lola’s father.
Chapter Four takes place at Rutgers University, where Oscar attends college in the years 1988 – 1992. Yunior starts the chapter by detailing how he got involved with the de Leóns when Lola takes care of him after he is jumped and beaten up. Lola is worried about Oscar because he tried to commit suicide at the end of the previous year. Yunior agrees to live with Oscar in the artsy dorm Demarest. Oscar and Yunior are unlikely friends, but they get along. When Yunior’s girlfriend dumps him because of his infidelity, Yunior decides to put his extra time and energy into shaping Oscar up so he can have a better chance at getting a girl, but Oscar loses interest part way through, and Yunior gets angry with him.
Then Oscar falls in love with a Puerto Rican goth girl named Jenni Muñoz. They spend a lot of time talking, but are never physically intimate. Jenni stops hanging out with Oscar when she finds a boyfriend, and Oscar acts out by tearing things off her wall and yelling at her. Soon after, he tries to commit suicide by jumping off a train bridge in New Brunswick. Before he jumps he sees the Golden Mongoose, and he survives the fall because he lands on the median. Oscar lives by himself for the fall semester of the next year, but then Yunior ends up in a relationship with Lola and moves back in with Oscar for the spring.
In the beginning of Section II, Lola talks about her last days in Santo Domingo with La Inca before she has to return home. Lola breaks contact with all friends, and makes $2000 by sleeping with an older man. She then gives the $2000 to Max’s family when he dies in a jaywalking accident.
Chapter five gives the details of Abelard Luis Cabral’s story, Belicia’s father and Oscar and Lola’s grandfather. He is a successful doctor married to a nurse. They have two daughters together. They live an affluent lifestyle and often socialize in the same circle as Trujillo. Their oldest daughter, Jacquelyn, develops into a beautiful woman. Abelard begins to fear that Trujillo will want to sleep with her (as he is known to do). Abelard consults his wife, Socorro, his mistress Lydia, and his friend Marcus, who all give their own opinions on the subject, but Abelard takes no action. When Abelard is asked pointedly to take Jacquelyn to a party, Abelard chooses not to obey the order. Soon after Abelard is arrested for a “Bad Thing” he said about Trujillo. The actual reason for his arrest is unclear—it could also have been about his refusal to let Trujillo have his daughter, or about a book he wrote that claimed that Trujillo has supernatural powers. Abelard is sentenced to 18 years in prison. Socorro then finds out she is pregnant with their third daughter Belicia. After Belicia is born, Socorro dies in an accident and Belicia is adopted by Socorro’s relatives, and is then passed on to another family to be their slave. Abelard’s other two daughters die in mysterious ways, and Abelard dies during his imprisonment. Beli is eventually rescued by La Inca, who finds Beli in a chicken coop with a terrible burn on her back. La Inca brings her to Baní, nurses her back to health and civilizes her.
Chapter Six takes place in the years after Oscar graduates from college, 1992 – 1995. Oscar returns to Paterson, New Jersey and lives with his mother. He gets a job teaching at his old high school, Don Bosco Tech. There he meets another teacher named Nataly who he becomes friends with and whom he fantasizes about, but she moves away. Oscar is very unhappy and depressed. After three years of this, Oscar decides one summer that he will go to Santo Domingo with his mother, tío, and sister.
The de Leóns go and stay with La Inca in La Capital where she now lives. Oscar has not been there in years and has forgotten how much he loves it—he especially loves how beautiful the women are. He decides to stay for an extra month. During that month, he falls in love with a semiretired prostitute named Ybón. He becomes good friends with Ybón, but like his other relationships, they are not physically intimate. Ybón has a boyfriend, the capitán, and he is in the national police force. One night when Oscar is driving them home from a bar, Ybón’s boyfriend pulls them over. As soon as they are pulled over Ybón jumps on Oscar and gives him his first kiss, which is witnessed by her boyfriend. Oscar is taken to a cane field and beaten, but he survives. Ybón is beaten as well, and she comes to visit Oscar to let him know she will be marrying her boyfriend. Oscar's mother books a flight for him to leave Santo Domingo.
When Oscar returns to New Jersey, he goes to visit Yunior in Washington Heights and he borrows money from Yunior. Oscar uses the money to fly back to the Dominican Republic and pursue Ybón. Oscar spends twenty-seven days there in pursuit, and also researches and writes a manuscript. At the end of the twenty-seven days, Oscar is taken to a cane field and shot by two men who work closely with the capitán.
After Oscar’s death, Yunior and Lola break up. A year after Oscar’s death, Belicia dies of cancer. Yunior describes his life in Perth Amboy, where he is married and teaches creative writing. He says he still sees Lola occasionally, and she is also married and has a daughter named Isis. Yunior hopes to tell Isis all about the history of her family, and to show her all of Oscar’s books and manuscripts.
Eight months after Oscar dies, Lola receives a package containing two manuscripts. One has a few chapters from a space opera Oscar was writing. The other is a letter to Lola in which Oscar says there will be another manuscript coming in the mail that will contain some sort of cure, perhaps to the fukú. The manuscript never arrives. Oscar also reveals that he was able to go on a trip alone with Ybón where he has sex with her and enjoys the intimacies of a romantic relationship.