The novel focuses on Maurice Bendrix, a rising writer during the Second World War in London, and Sarah Miles, the wife of an impotent civil servant. Bendrix is loosely based on Greene himself, and he reflects often on the act of writing a novel. Sarah is based loosely on Greene's mistress at the time, Catherine Walston, to whom the book is dedicated.
Bendrix and Sarah fall in love quickly, but he soon realises that the affair will end as quickly as it began. The relationship suffers from his overt and admitted jealousy. He is frustrated by her refusal to divorce Henry, her amiable but boring husband. When a bomb blasts Bendrix's flat as he is with Sarah, he is nearly killed. After this, Sarah breaks off the affair with no apparent explanation.
Later, Bendrix is still wracked with jealousy when he sees Henry crossing the Common that separates their flats. Henry has finally started to suspect something, and Bendrix decides to go to a private detective to discover Sarah's new lover. Through her diary, he learns that, when she thought he was dead after the bombing, she made a promise to God not to see Bendrix again if He allowed him to live again. Greene describes Sarah's struggles. After her sudden death from a lung infection brought to a climax by walking on the Common in the rain, several miraculous events occur, advocating for some kind of meaningfulness to Sarah's faith. By the last page of the novel, Bendrix may have come to believe in a God as well, though not to love Him.
The End of the Affair is the fourth and last of Greene's explicitly Catholic novels.