Famed novelist Paul Sheldon (James Caan) is the author of a successful series of novels involving a character called Misery Chastain. But Paul wants to branch out and has just finished the manuscript of a new unrelated novel. He departs from Silver Creek, Colorado to head west but is caught in a blizzard and his car goes off the road. He is rescued by a nurse, Annie Wilkes (Kathy Bates), and brought to her remote home. Both of Paul's legs are broken and he has a dislocated shoulder, so he is bedridden and incapacitated. Annie claims she is his 'number one fan' and talks a lot about him and his novels. She is happy when Paul lets her read his new novel, but later admits she disliked the excessive swearing. While feeding him, she is angered and spills soup on him but regains control and apologizes. She buys a copy of Paul's latest book, Misery's Child, but after learning that he has "killed off" Misery, Annie flies into a rage, almost smashing a table on Paul's head. She reveals that nobody knows where he is (contradicting what she had earlier told him). Annie leaves and Paul tries to escape from his room, but she has locked the door.
The next morning, Annie makes Paul burn his latest manuscript. When he is well enough to get out of bed, she insists he write a new novel entitled Misery's Return in which he brings the character back to life. Paul reluctantly does, believing Annie might kill him otherwise. However, having found a means of escaping his room, he sneaks out whenever Annie is away and begins to stockpile his painkillers. He tries to kill Annie during a candlelit dinner, but is foiled when she accidentally spills her drugged wine. During another escape attempt, Paul finds a scrapbook of newspaper clippings about his disappearance and Annie's past. He discovers that she was suspected and tried for several infants' deaths. Later, Annie drugs Paul and straps him to the bed. When he wakes, she tells him that she knows he's been out of his room and breaks his ankles with a sledgehammer in an act of "hobbling".
Meanwhile, the local Sheriff (Richard Farnsworth) is investigating Paul's disappearance and visits Annie, prompted by discovering a quote she used from a Misery book during her trial years earlier. While there, he finds that Paul has been drugged and hidden in the basement. Annie shoots and kills him; she tells Paul that they must die together. He agrees, but says he wants to finish the novel and "give Misery back to the world". When the book is done, he tells Annie it was his habit after ending a novel to have a cigarette and a glass of champagne. Later, he sends her to get a second glass. When Annie returns, he sets the book on fire. She tries to put out the fire, but Paul hits her head with the typewriter. Annie shoots him in the shoulder and he lunges at her. During the ensuing fight, Paul trips Annie, causing her to land head-first on the typewriter. Annie lunges at him, but he strikes her over the head with a small steel pig statue, killing her.
Eighteen months later, Paul (now walking with a cane) meets his publishing agent Marsha (Lauren Bacall) in a restaurant and discusses his first non-Misery novel, titled The Higher Education of J. Philip Stone, which has become a success. Marsha asks if he wants to write a non-fiction book about his captivity, but Paul is non-committal. While at the restaurant, he sees a waitress whom he briefly imagines as Annie. The waitress claims she is his 'number one fan', to which Paul responds, "That's very sweet of you."
