The novel focuses on William Stoner and the central figures in his life. Those who become his enemies are used as tools against him who separate Stoner from his loves. New Yorker contributor Tim Kreider describes their depictions as "evil marked with deformity."
- William Stoner: The novel's main character, called "Stoner" throughout the book, is a farm boy turned English professor. He uses his love of literature to deal with his unfulfilling home life.
- Edith Stoner: Stoner's wife, a neurotic woman from a strict and sheltered upbringing. Stoner falls in love with the idea of her, but soon realizes that she is bitter and has been long before they were married.
- Grace Stoner: Stoner and Edith's only child. Grace is easily influenced by her mother. Edith keeps Grace away from and against her father as a sort of "punishment" for Stoner, because of the couple's failing relationship.
- Gordon Finch: Stoner's colleague and only real ally and friend. He has known Stoner since their graduate school days and becomes the dean of the college of Arts and Sciences. His affable and outgoing demeanor contrasts that of Stoner.
- David Masters: Stoner's friend from graduate school. He is killed in action during the Great War, but his words have a continuing impact on Stoner's worldview.
- Archer Sloane: Stoner's teacher and mentor growing up. He inspired Stoner to leave agriculture behind and begin studying English literature. He is old and ailing by the time Stoner is hired at the university.
- Hollis Lomax: Sloane's "replacement" at the university. He and Stoner began as friends, but Stoner eventually sees him as an "enemy". Stoner and Lomax do not see eye to eye in their work life. Described as a hunchback.
- Charles Walker: Lomax's crippled mentee, an arrogant and duplicitous young man who uses rhetorical flourish to mask his scholarly ineptitude. Also becomes an enemy to Stoner.
- Katherine Driscoll: A younger teacher, with whom Stoner falls in love and has an affair. University politics and circumstantial differences keep them from continuing a relationship.