The novel begins at 6:27 a.m., New Year's Day, 1975. 47-year-old Archie Jones is sat in his car trying to kill himself through carbon monoxide poisoning when he remembers the look of a beautiful woman he once saw framed in a doorway. "If there was any chance of ever seeing a look like that again, then he wanted the second chance."
Archie abandons his suicide attempt and goes to the "End of the Wold Party." There, he falls in love with a young Jamaican woman called Clara Bowden. The two marry and have a daughter called Irie.
Archie and Clara form an unlikely close relationship with the Bengali Muslim couple Samad and Alsana Iqbal. Archie met Samad in World War two where they were both part of the same tank fleet. Samad and Alsana were the only guests at Clara and Archie's wedding. When their children grow up, they attend the same schools.
Samad and Alsana's marriage is put under strain after Samad has an affair with his sons' music teacher and, with the help of Archie, secretly sends his son, Magid, to Bangladesh.
In 1990, the now-teenage Irie has fallen in love with Samad and Alsana's son, Millat. At school, she tries to warn him about the school clamping down on marijuana smoking, but she gets caught smoking a joint with him. As punishment, they have to study twice a week at the Chalfen's house. Their grades improve so much that their parents hold a party in their honor.
Clara thinks back to the early 20th century in Jamaica, when an Englishman called Captain Charlie Durham impregnated her grandmother, Ambrosia. She gave birth to Clara's mother during an earthquake. Durham tried to get Ambrosia and their child a place on the rescue ships, but they were refused entry. Durham's subsequent complaints lead to the rescue ships leaving thousands stranded on the island.
Back in the present, Millet has become a member of an Islamic Fundamentalist group, and Irie is beginning to reconnect with her Jamacian heritage. She is delighted when her grandmother, Hortense, invites her to Jamaica for Judgement Day 2000.
Magid returns to London, and his brother refuses to talk to him because he supports an animal testing project called FutureMouse. Irie tries to get the two brothers back together, but she only ends up having sex first with Millat and then with Magid.
The novel concludes at the FutureMouse conference on New Year's Eve, 1992. In the name of his fundamentalist group, Millat tries to shoot the scientists, but Archie jumps in front of him and takes a bullet in the thigh, landing on the glass case holding the mouse.
For the shooting, both Magid (he was confused for Millat) and Millat get community service. The novel ends with Irie leaving for Jamaica.