Rabbit, Run is the story of Harry "Rabbit" Angstrom, a former high school basketball star living in Brewer, Pennsylvania with his pregnant wife and two-year-old son. Harry experiences a crisis of self that leads him to abandon his family and make many abortive attempts to "find" himself. Harry repeatedly pressures women for sex, attempting to exert control over his life even as it loses all form and purpose. At the novel's end his newborn child dies in an accident and Harry's fate is left uncertain.
Harry "Rabbit" Angstrom is 26, has a job selling a kitchen gadget named MagiPeeler, and is married to Janice, a former salesgirl at the store where he worked who is currently pregnant. They have a two-year-old son named Nelson, and live in Mount Judge, a suburb of Brewer, Pennsylvania. He believes that his marriage is corrupt and something is missing from his life: having been a basketball star in high school, Harry finds his middle-class family life unsatisfying. On the spur of the moment, he decides to leave his family and drive south in an attempt to "escape". However, after getting lost, he returns to his home town. 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 soon moves into her apartment. During this time, Janice moves back into her parents' house and the local Episcopal priest, Jack Eccles, befriends Harry in a futile attempt to get him to reconcile with his wife. Nonetheless, Harry remains with Ruth until the night he learns that she had a fling with his high school nemesis, Ronnie Harrison. Enraged, Harry pressures 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.
Reunited with Janice, Harry returns home with her and their daughter, named Rebecca June. Harry attends church one morning and, after walking the minister's wife Lucy home, interprets her invitation to come in for a coffee as a sexual invitation. 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 leaves, yet again, 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 new departure, Janice gets drunk and accidentally drowns Rebecca June in the bath tub. 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 immediately, although in a somewhat aloof way. 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 by him. Though Harry is relieved to discover she has not had an abortion, he is unwilling to divorce Janice. 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.