Archie Jones, a middle-aged Englishman, is slumped in a car in Northern London on January 1, 1975, attempting to commit suicide by suffocating in the fumes. His Italian wife, Ophelia, who suffers from an unknown mental illness, has just divorced him after 30 years of marriage. He is inadvertently saved by Mo Hussein-Ishmael, the neighborhood butcher, who insists that his property is not “licensed” for suicides; Archie takes this as a sign of his own redemption. Reenergized, he drives past an “End of the World” New Year’s party and decides to stop by. There, he meets Clara Bowden, the 19-year-old daughter of a Jamaican immigrant, the devout Jehovah’s Witness Hortense Bowden. Six weeks after meeting, Clara and Archie are married.
A prolonged flashback explores Clara’s childhood and her relationship with Ryan Topps, an unappealing but rebellious boy in her high school. Though Clara is drawn to Ryan for his deviance from the religious tenets she has been taught, Ryan begins to spend more time with Hortense than Clara, and he eventually becomes a Jehovah’s Witness. Clara, though, continues to smoke, drink, and attend parties, until she meets Archie in 1975. Clara is disappointed by her marriage, quickly realizing that Archie is a “dull man.” Nonetheless, she makes friends with Archie’s best friend Samad Iqbal, whom he met when both men served as soldiers in Eastern Europe in World War II, and Samad’s wife Alsana. The two families’ children grow up together in Willesden, London.
Both Samad and Archie have found low-level employment after their careers in the military: Archie in a paper-folding company, Samad in a West End curry house. The men content themselves with frequent trips to their beloved pub, O’Connell’s. Samad, though, is particularly upset with his lifestyle in London, since he believes that he is destined for greater things: he is obsessed with the story of his great-grandfather, Mangal Pande, a Hindu soldier known for firing the first shot of the Indian Rebellion of 1857. Alsana, whose marriage to Samad was arranged, is also dissatisfied with her own life, since she is forced to work hard to make ends meet. She befriends Clara, and the two women become pregnant at the same time (Alsana with identical twins).
Through a flashback, Samad and Archie are revealed to have been relatively unimportant soldiers in World War II, part of the “Buggered Battalion,” a squad of misfit soldiers stationed in Bulgaria. After the rest of the regiment is accidentally killed, Samad and Archie encounter Dr. Marc-Pierre Perret, or “Dr. Sick,” a Nazi collaborator. Samad wants his wartime experiences to measure up to Mangal Pande’s (supposedly) courageous actions, and he insists that Archie kill Dr. Sick.
The novel skips forward to 1984. The Bowden and Iqbal children are in primary school, and Samad begins an affair with Poppy Burt-Jones, the school’s music teacher. Tormented by his own inability to follow Islam’s teachings, Samad decides to send his son Magid to Bangladesh—an attempt to restore his family’s connection to their faith and culture. Meanwhile, Millat, Magid’s twin, becomes a rebellious womanizer as he grows up, though he eventually devotes himself to KEVIN (“Keepers of the Eternal and Victorious Islamic Nation”), a fundamentalist Muslim brotherhood based in London.
Meanwhile, Irie, Clara and Archie’s daughter, struggles with her identity and personal development while harboring a secret crush on Millat, with whom she has grown up in Willesden. Irie, Millat, and a classmate, Joshua Chalfen, are caught with marijuana at school, and as punishment, Irie and Millat are forced to attend study sessions at Joshua’s home. There, they meet Joshua’s middle-class intellectual parents, Joyce and Marcus; Marcus is working on a project called “FutureMouse,” manipulating the genes of a test mouse in order to cause cancer progression, effectively eliminating genetic chance. While Joshua grows more distant from his family, ultimately joining an animal rights group called FATE (“Fighting Animal Torture and Exploitation”), Millat grows closer to the Chalfens, particularly Joyce, who hopes to save him from his reckless, wanton lifestyle. After expressing a desire to take a year off after high school to visit Africa, Irie gets into an argument with Clara. She leaves for her grandmother’s house, where she lives temporarily with Hortense and Ryan Topps, who has become Hortense’s live-in aide.
Magid returns from Bangladesh, where he began a correspondence with Marcus Chalfen, helping him to develop and market the FutureMouse project. The mouse is set to be unveiled at the Perret Institute in London on December 31, 1992. Millat, unimpressed by Magid’s newfound atheism and intellectualism, refuses to see his brother, and the two become estranged. Irie tries to convince Millat to meet with Magid; later, she and Millat have sex, though Millat is horrified by his own actions, which contradict his fundamentalist beliefs. Almost immediately after, Irie has sex with Magid.
Different threads of narrative converge at the announcement of the FutureMouse project on New Year’s Eve, where KEVIN, FATE, Archie, Samad, and Irie gather. Both KEVIN and FATE are protesting the project, though Millat and Joshua are beginning to feel disconnected from their respective causes. Millat brings a gun with him, ostensibly to shoot at the project’s directors, and as the event begins, Archie realizes that he recognizes one of these directors, Marcus’s mentor: he is Dr. Marc-Pierre Perret, or Dr. Sick. Millat stands up to shoot at the doctor, and Archie blocks the path of the bullet with his own body. The novel then shifts back to World War II: Archie is revealed to have saved Dr. Perret’s life, based on a coin flip (and unbeknownst to Samad). Back in the present, Archie is struck in the thigh by Millat’s bullet, and the FutureMouse escapes from its cage.
Both Magid and Millat are sentenced to community service, since witnesses are unable to identify the perpetrator of the attempted assassination. Joshua and Irie begin dating, and they raise Irie’s daughter together (though the identity of the child’s father—either Magid or Millat—is never revealed). O’Connell’s pub opens up to women for the first time in 1999, and Clara and Alsana join their husbands there.