On New Year's Day 1975, an Englishman named Archie Jones, a 47-year-old man whose disturbed Italian wife has just walked out on him, is attempting to commit suicide 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, antisocial Ryan Topps, but their relationship falls apart after Ryan becomes a member of the Jehovah's Witnesses. Archie and Clara are soon married and have a daughter, Irie, who grows up to be intelligent but with low self-confidence.
Also living in Willesden, North-West 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. 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. Following the war, Samad emigrated to Britain and married Alsana Iqbal, née Begum, in a traditional arranged marriage. Samad is a downtrodden waiter in a West End curry house, and is obsessed by the history of his great-grandfather, Mangal Pandey, who allegedly fired the first shot of the Indian Rebellion of 1857 (and missed). 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 masturbation, 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. Ironically, and to Samad's fury, Magid becomes an Anglicized atheist and devotes his life to science. Millat, meanwhile, pursues a rebellious path of womanizing and drinking – as well as harbouring a love of mob movies such as The Godfather and Goodfellas. Angry at his people's marginalization in English society Millat demonstrates against Salman Rushdie 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 Jewish-Catholic family of Cambridge educated intellectuals who typify a distinctive strain of North London liberal trendiness. The father, Marcus Chalfen, is a university lecturer and geneticist working on a controversial 'FutureMouse' project in which he introduces chemical carcinogens into 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 predetermined 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. However, this sympathy comes at the expense of their own son, Joshua, whose difficulties are ignored by his parents. Originally a well-moulded "Chalfenist", Joshua later 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' research assistant on the FutureMouse project, while Millat becomes further involved in KEVIN. Irie, who has been working for Marcus, briefly succeeds in her long-hidden attraction to Millat but is rejected under his KEVIN-inspired beliefs. Irie believes that Millat cannot love her, for he has always been "the second son" both symbolically and literally; Millat was born two minutes after Magid. Irie makes Magid the "second son" for a change by sleeping with him right after her romantic encounter of Millat. This causes her to become pregnant, and she is left unsure of the father of her child, as the brothers are identical twins.
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 beliefs – at its exhibition on New Year's Eve 1992. At the Perret Institute, Hortense and the other Jehovah's Witnesses sing loudly in the hallway. Samad goes out to hush them, but when he arrives, doesn't have the heart to make them stop. When he returns, it suddenly strikes him 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. Without thinking, Archie jumps in front of him and takes a bullet in the thigh. As he falls, he knocks over the mouse's glass cage, and it escapes.
At the novel's end, the narrator presents us with different "endgames" in the style of television. Magid and Millat both serve community service for Millat's crime, since witnesses identify both as the culprit. Joshua and Irie end up together and join Hortense in Jamaica in the year 2000. Mickey opens up the previously men-only O'Connell's pub to women, and Archie and Samad finally invite their wives along with them.