Harry "Rabbit" Angstrom, formerly a high school basketball star, is now 26 and has a job selling a kitchen gadget named MagiPeeler. He is married to Janice, who was a salesgirl at the store where he once worked, and who is now pregnant. They live in Mount Judge, Pennsylvania, a suburb of Brewer, and have a two-year-old son named Nelson. Harry finds middle-class family life unsatisfying, and on the spur of the moment, leaves his family and drives south in an attempt to "escape". After getting lost, he returns to his home town, but not wanting to return to his family, he instead visits his old basketball coach, Marty Tothero.
That night, Harry has dinner with Tothero and two girls, one of whom, Ruth Leonard, is a part-time prostitute. Harry and Ruth begin a two-month affair, and he moves into her apartment. Meanwhile, Janice moves back in with her parents. The local Episcopal priest, Jack Eccles, tries to persuade Harry to reconcile with his wife. But Harry stays with Ruth until he learns she had a fling with his high school nemesis, Ronnie Harrison. Enraged, Harry coaxes Ruth into performing fellatio on him. The same night, Harry learns that Janice is in labor, and he leaves Ruth to visit his wife at the hospital.
Reconciled with Janice, Harry moves back into their home where their newborn daughter, Rebecca June, awaits them. Harry attends church one morning and, after walking the minister's wife Lucy home, interprets her invitation to come in for coffee as a sexual advance. When he declines the invitation for coffee, stating that he has a wife, she angrily slams the door on him. Harry returns to his apartment and, happy about the birth of his daughter, tries to reconcile with Janice. He encourages her to have a whiskey, then, misreading her mood, pressures her to have sex despite her postnatal condition. When she refuses and accuses him of treating her like a prostitute, Harry masturbates onto her and then leaves in an attempt to resume his relationship with Ruth. Finding her apartment empty, he spends the night at a hotel.
The next morning, still distraught at Harry's treatment of her, Janice gets drunk and accidentally drowns Rebecca June in the bathtub. The other main characters in the book except Harry soon learn of the accident and gather at Janice's parents' home. Later in the day, unaware of what has happened, Harry calls Reverend Eccles to see how his return home would be received. Reverend Eccles shares the news of his daughter's death, and Harry returns home. Tothero later visits Harry and suggests that the thing he is looking for probably does not exist. At Rebecca June's funeral, Harry's internal and external conflicts result in a sudden proclamation of his innocence in the baby's death. He then runs from the graveyard, pursued by Jack Eccles, until he becomes lost.
Harry returns to Ruth and learns that she is pregnant. Though Harry is relieved to discover she has not had an abortion, he is unwilling to divorce Janice. In his apparent final attempt to salvage his relationship with Ruth, he decides to find her and make empty promises.
Harry abandons Ruth, still missing the feeling he has attempted to grasp during the course of the novel; his fate is uncertain as the novel concludes.
