The story deals with the life of T. S. Garp. His mother, Jenny Fields, is a strong-willed nurse who wants a child but not a husband. She encounters a dying ball turret gunner known only as Technical Sergeant Garp, who was severely brain damaged in combat. Jenny nurses Garp, observing his infantile state and almost perpetual autonomic sexual arousal. As a matter of practicality and kindness in making his passing as comfortable as possible and reducing his agitation, she manually gratifies him several times. Unconstrained by convention and driven by practicality and her desire for a child, Jenny uses Garp's semen to impregnate herself and names the resulting son "T. S." (a name derived from "Technical Sergeant", but consisting of just initials). Jenny raises young Garp alone, taking a position at the all-boys Steering School in New England.
Garp grows up, becoming interested in sex, wrestling, and writing fiction—three topics in which his mother has little interest. After his graduation in 1961, his mother takes him to Vienna, where he writes his first novella. At the same time, his mother begins writing her autobiography, A Sexual Suspect. After they return to Steering, Garp marries Helen, the wrestling coach's daughter, and begins his family, he a struggling writer, she a teacher of English. The publication of A Sexual Suspect makes his mother famous. She becomes a feminist icon, as feminists view her book as a manifesto of a woman who does not care to bind herself to a man, and who chooses to raise a child on her own. She nurtures and supports women traumatized by men, among them the Ellen Jamesians, a group of women named after an eleven-year-old girl whose tongue was cut off by her rapists to silence her. The members of the group cut off their own tongues in support of the girl.
Garp becomes a devoted parent, wrestling with anxiety for the safety of his children and a desire to keep them safe from the dangers of the world. He and his family inevitably experience dark and violent events through which the characters change and grow. Garp learns (often painfully) from the women in his life (including transsexual ex-football player Roberta Muldoon), who are struggling to become more tolerant in the face of intolerance. The story contains a great deal of (in the words of Garp's fictional teacher) "lunacy and sorrow", and the sometimes ridiculous chains of events the characters experience still resonate with painful truth.
The novel contains several framed narratives: Garp's first novella, The Pension Grillparzer; "Vigilance", a short story; and the first chapter of his novel, The World According to Bensenhaver. The book also contains some motifs that appear in almost all John Irving novels: bears, New England, Vienna, wrestling, people who are uninterested in having sex, and a complex Dickensian plot that spans the protagonist's whole life. Adultery (another common Irving motif) also plays a large part, culminating in one of the novel's most harrowing and memorable scenes. Another familiar Irving trope, castration anxiety, is present, most obviously in the fate of Michael Milton.