At the start of Rabbit, Run, Harry "Rabbit" Angstrom, a 26-year-old who once shined as a high school basketball star, is heading back from his unsatisfactory job demonstrating the MagiPeel vegetable peeler. During his commute, he notices some kids playing basketball, joins them, and reminisces about his past successes. He then returns to his cramped and shabby apartment. There, his pregnant wife Janice is watching TV and drinking. She asks Rabbit to retrieve their car, pick up their son Nelson, and buy her some cigarettes. These tasks add to Rabbit's sense of being trapped and discontented with his job, marriage, and life. When he sees his son through the window at his in-laws' house, he impulsively decides to leave Nelson with them. He then drives south, eager to escape his old life.

As Rabbit takes smaller and smaller roads, he becomes lost. Seeking directions, he receives only cryptic advice: one man tells him, "The only way to get somewhere, you know, is to figure out where you're going before you get there." Eventually, feeling defeated, exhausted, and isolated, he turns back and heads home. Unwilling to face his wife and son, he seeks refuge with his former coach, Marty Tothero.

Tothero, who has a young girlfriend, arranges for her to bring along a friend named Ruth, and the four of them go out to dinner. Rabbit ends up going home with Ruth, who works part-time as a prostitute, and spontaneously decides to live with her. He sneaks back to his apartment to collect his clothes. Although Janice isn't there, Jack Eccles, the minister from Janice's parents' church, catches him. Eccles tries to persuade Rabbit to return to his family, but fails. However, he schedules a golf game with Rabbit for the following week. Rabbit understands this is a way for Eccles, and indirectly Janice's family, to monitor him and potentially coax him back home, but he agrees to meet anyway.