A celebrated novelist, Paul Sheldon, known for his popular Victorian-era romance series featuring the character Misery Chastain, completes his latest manuscript at a remote Colorado hotel. Wanting to bid farewell to the series and pursue new creative avenues, Sheldon drives back to New York. However, a severe blizzard causes him to lose control of his car, and he suffers a serious car accident in the mountains. Injured and unconscious, he is rescued by Annie Wilkes, a local nurse and self-proclaimed "number one fan" of his Misery novels. Grateful for her help, he soon realizes his savior has brought him to her remote home to recuperate from his injuries.

As he recovers, it becomes increasingly clear that the nurse harbors a dangerous obsession with Sheldon and his work. Sheldon finds himself imprisoned by Wilkes, who has not only a deep attachment to the character of Misery Chastain but also an intense emotional instability. She reacts violently when she learns that Sheldon has killed off her favorite character in his unreleased manuscript and withholds pain medication to force him to write a new book that brings Misery back to life. As Sheldon is compelled to write under distressing circumstances, he strategizes on how to survive his captivity while keeping Wilkes appeased enough not to harm him and to remain hopeful for eventual rescue.