On New Year's Day 1975, Archie Jones, a 47-year-old Englishman whose disturbed Italian wife has just walked out on him, attempts to take his own life by gassing himself in his car when a chance interruption causes him to change his mind. Filled with a fresh enthusiasm for life, Archie flips a coin and then finds his way into the aftermath of a New Year's Eve party. There he meets the much-younger Clara Bowden, a Jamaican woman whose mother, Hortense, is a devout Jehovah's Witness. Clara had been interested in the unattractive, anti-social Ryan Topps, but their relationship falls apart after Ryan becomes a member of the Jehovah's Witnesses and grows close to her mother. Archie and Clara are soon married and have a daughter, Irie, who grows up to be intelligent but with low self-confidence due to her morbid obesity and insecurity about her mixed-race identity.
Also living in Willesden, London, is Archie's best friend Samad Iqbal, a Bengali Muslim from Bangladesh; the two men spend much of their time at the O'Connell's pub arguing with the owner, Mickey, a Muslim whose entire extended family all suffer from cystic acne. Archie and Samad met in 1945 when they were part of a tank crew inching through Europe in the final days of World War II, though they missed out on the action. Their friendship was cemented when Archie, acting at Samad's behest, apparently executed an escaped Nazi scientist whom they had been tasked with turning over to the authorities. Following the war, Samad emigrated to Britain and married Alsana Iqbal, née Alsana Begum, or "Miss Alsana", in a traditional arranged marriage. Samad is a downtrodden waiter in a West End curry house, and is obsessed by the history of his supposed but unlikely great-grandfather, Mangal Pandey, a Hindu soldier from Uttar Pradesh, not Bengal, who is famous for firing the first shot of the Indian Rebellion of 1857 (though he missed and was executed). Samad and Alsana have twin boys, Magid and Millat, who are the same age as Irie. Samad in particular finds it difficult to maintain his devotion to Islam in an English life; he is continually tormented by what he sees as the effects of this cultural conflict upon his own moral character—his Muslim values are corrupted by his compulsive masturbation, beer drinking, and his affair with his children's music teacher, Poppy Burt-Jones. In an attempt to preserve his traditional beliefs, he sends 10-year-old Magid to Bangladesh in the hope that he will grow up properly under the teachings of Islam. From then on, the lives of the two boys follow very different paths. To Samad's fury, Magid becomes an Anglicised atheist and devotes his life to science. Millat, meanwhile, pursues a rebellious path of womanising, drinking and petty hooliganism—as well as harbouring a love of mob movies such as The Godfather and Goodfellas. Angry at his people's marginalisation in English society, Millat demonstrates against Salman Rushdie for his novel The Satanic Verses in 1989 and eventually pledges himself to a militant Muslim fundamentalist brotherhood known as "Keepers of the Eternal and Victorious Islamic Nation" (KEVIN).
The lives of the Joneses and Iqbals intertwine with that of the white, middle-class Chalfens, a lapsed Jewish-Catholic family of Oxbridge-educated intellectuals who typify a distinctive strain of North London liberal trendiness, and who are recruited by Irie and Millat's school to tutor them after the pair are caught smoking marijuana. The father, Marcus Chalfen, is a university lecturer and geneticist working on a controversial 'FutureMouse' project in which he introduces chemical carcinogens into the body of a mouse and is thus able to observe the progression of a tumour in living tissue. By re-engineering the actual genome and watching cancers progress at pre-determined times, Marcus believes he is eliminating the random. The mother, Joyce Chalfen, is a horticulturist and part-time housewife with an often entirely misguided desire to mother and 'heal' Millat as if he were one of her plants. To some extent, the Chalfen family provides a safe haven as they (believe themselves to) accept and understand the turbulent lives of Irie, Magid, and Millat. Irie finds herself working for Marcus as a secretary, Marcus takes an intellectual interest in Magid and subsidizes his flight home, and even Millat's grades slightly improve.
However, both Alsana and Clara become suspicious of their children constantly spending time at the Chalfens, and Joyce and Marcus's arrogance antagonize both Clara and the Iqbal family. The Chalfens' actions also comes at the expense of their own son, Joshua, whose difficulties are ignored by his parents. Originally a well-moulded "Chalfenist", Joshua rebels against his father and his background by joining the radical animal rights group "Fighting Animal Torture and Exploitation" (FATE). Meanwhile, after his return from Bangladesh, Magid works as Marcus's research assistant on the FutureMouse project, while Millat becomes further involved in KEVIN. Irie, who has been attracted to Millat since adolescence, has a one-night-stand with him, only for him to reject her due to his KEVIN-inspired beliefs about ritual purity. Dejected, Irie immediately seduces Magid. This causes her to become pregnant, but she is left unsure of the child's paternity, as the brothers are identical twins and therefore share the same DNA.
The strands of the narrative grow closer as Millat and KEVIN, Joshua and FATE, and Clara's mother Hortense and the Jehovah's Witnesses all plan to demonstrate their opposition to Marcus's FutureMouse—which they view as an evil interference with their own religious and ethical beliefs—at its exhibition on New Year's Eve 1992. At the Perret Institute, Hortense and the other Jehovah's Witnesses sing loudly in front of the building. Samad goes out to hush them, but when he arrives he cannot summon the heart to make them stop. When he returns, he realizes that the founder of the Perret Institute and the oldest scientist on Marcus Chalfen's panel is Dr. Perret, the Nazi he captured during World War II. Enraged that Archie did not kill him all those years ago, Samad runs over and begins cursing Archie. Just then, Millat advances on the table of scientists with a gun. Not wanting Millat to become a murderer, Archie jumps in front of him and takes a bullet in the thigh. As he falls, he crushes the mouse's glass cage, and it escapes.
At the novel's end, the narrator presents us with different "end games" in the style of a television series finale: since witnesses identify both as the culprit, Magid and Millat are both sentences to community service working at a new garden project of Joyce's. Joshua and Irie end up together and join Hortense in Jamaica in the year 2000 with Irie's daughter, who remains ignorant of her true parentage and regards Magid and Millat as her uncles. Mickey opens up the previously men-only O'Connell's pub to women, and Archie and Samad finally invite their wives along with them to celebrate the new millennium.
