The novel opens, aptly enough, with a basketball game being played by a few children on a street in Mt. Judge - the suburban home of our hero, Harry Angstrom. When Harry - nicknamed "Rabbit" for his awkward looks - appears, he is wearing a business suit and is headed home. He was once the star athlete of his high school, a great basketball player prized by his team and his coach, Marty Tothero. Now he is twenty-six, stuck in an unhappy marriage and an unfulfilling job selling kitchen gadgets. He joins the game for a bit, and then continues on his way.
At home, his newly pregnant wife, Janice, irritates him so much that when she sends him on an errand, Rabbit instinctively drives his car out of Mt. Judge and onto the interstate highway. He doesn't know where he's headed - he is only aware that he needs to escape. He makes it as far south as West Virginia before he finally turns around and heads home. Back in Mt. Judge, he joins Marty Tothero - now just as "washed-up" and as much of a "has-been" as Rabbit, having been fired years ago from his job at the high school due to a "scandal" - and hits the town with his former coach. He meets Ruth Leonard on a double date with Marty, and winds up spending the night with her in her apartment. He grows very affectionate of her, and, though Ruth's opinion of Rabbit fluctuates, the two live together for a solid two months.
During that time, the young local minister, Jack Eccles, tries to do his part in saving Rabbit's marriage. Originally set on his trail by Janice's angry parents, Jack ends up befriending Rabbit and sincerely trying to help him become a better person. Rabbit more or less dismisses Jack's efforts, but when Janice finally goes into labor he hastily leaves Ruth and goes to the hospital. That night, after seeing Janice (and perhaps rediscovering his love for her), Rabbit feels as if he has started a new life. He thanks Eccles, and puts the affair with Ruth behind him.
Things, however, rapidly go sour. The new baby girl - named Rebecca after Janice's mother - cries nonstop, and Rabbit finds himself consumed with lust for his wife, who is now more or less incapable of having sex. One night, after Rabbit tries to make love to Janice only to have her snap at him - "I'm not your whore" - he walks out and wanders the town. Janice becomes wracked with fear and despair, certain that Rabbit has left her again, maybe for good this time. She drinks excessively throughout the ensuing day, and finally, in a drunken hysteria, accidentally drowns Rebecca in the bathtub.
When Rabbit hears the news, he goes to the home of Janice's parents, where she is staying. He tells her it was his fault, and the two finally seem united in a true bond. After the funeral, however, Rabbit becomes filled with the sense that he finally understands everything - a sort of skewed religious awakening - and lashes out inexplicably at his wife: "Don't look at me...I didn't kill her." He then runs away, finally winding up back at Ruth's apartment. She is pregnant, and the father, it seems, is Rabbit. He is overjoyed that she has not aborted the baby, and insists that he would love to marry her. She delivers an ultimatum: divorce Janice, or she and the baby are "dead" to him. He agrees to these terms, and runs out to grab some food. Once outside the apartment, however, doubts immediately start to plague him. How can he divorce Janice? What is to become of their son - a two year-old boy named Nelson? It all proves too much for Rabbit. With "a kind of sweet panic growing lighter and quicker and quieter," he does what he has always done: he runs away.