William Stoner is born into a farming family in rural Missouri in the late 1800s. He attends University and falls in love with English literature. He becomes a professor and teaches for decades through numerous personal and political struggles until his death. In his early life, Stoner knew only the farm and had scarcely traveled more than several miles away from it. When he is twenty he goes to the University of Missouri to study agriculture but winds up changing majors when he falls in love with English. Before his graduation, one of his teachers, Archer Sloane, sensing his love for literature, suggests that Stoner continue his studies and obtain his doctoral degree and Stoner accepts. Two of his friends, David Masters and Gordon Finch, leave the university to enlist and fight in World War I. They urge that he come along, but he decides against it after consulting with Sloane, who argues that armed conflict is antithetical to the creative, civilizing work of the intellectual. David Masters is killed in combat.

Stoner finishes his degree and is offered a job teaching at the University; he readily accepts. With the war over, veterans begin flooding back to the campus, including Finch. At a party thrown in their honor, Stoner meets Edith Bostwick and is immediately captivated by her. After a brief courtship and a visit to meet her parents, the two marry. They have problems from the start and she seems disgusted by him. She warms up to him only when she decides she wants a child and she ultimately gives birth to a daughter, Grace. She returns to her withdrawn self and most of the parental duties fall on Stoner.

The department is shaken up when Sloane dies of a heart attack. He was the director of the department and Gordon Finch, a dean now, fills in for him temporarily and hires on Hollis Lomax a young professor who suffers from an unfortunate deformity. Stoner is immediately drawn to him and when he comes to Stoner's house-warming party, the two find they have much in common intellectually.

Edith's father commits suicide at the onset of the Great Depression and she travels home for the funeral and while there undergoes a great change. She destroys everything her father gave to her and returns home with a new look. Stoner has also changed and found himself developing into the kind of teacher he had always wanted to be. Immediately, she finds every way to make his life miserable and even keeps Grace away from him.

Meanwhile, Stoner has an encounter with a graduate student named Charles Walker. Walker, a cripple, has been recommended to a seminar Stone is teaching by Lomax. Walker proves to be a poor student and an annoyance during the course and Stoner winds up failing him. Later, Stoner sits on the committee to determine whether Walker will continue his work at the university and insists that he be expelled. Lomax, however, sympathetic to the student, uses his new political clout as head of the English department to override Stoner's decision and develops a lifelong grudge against him.

During this time, Stoner begins to have a very fulfilling extramarital relationship with his former student, Katherine. The two, though shy initially, find great joy in one another, both intellectually and physically. Edith finds out about his affair but does not seem to particularly care. When Lomax finds out about it, however, he sees it as a valuable opportunity to punish Stoner and forces the two to break up. Katherine leaves the University and he never sees her again.

Stoner cleverly tricks Lomax into giving him a favorable schedule and, as he ages, he becomes a kind of living legend around campus, known for his various eccentricities. Meanwhile Grace, now an attractive young woman in college, announces that she is pregnant. At her mother's urging, she marries the father, who dies shortly before the birth in World War II. Grace develops a severe drinking problem and the child is raised by the father's parents. Not long after, Stoner, now in his sixties, finally decides to retire after the doctor finds a tumor in his intestines. His last days are spent in a dream-like state, his lucidity dwindling gradually. In his last moments, he looks at his only published book and dies.