Misery is the story of author Paul Sheldon, writer of a series of popular Regency-era romance novels starring heroine Misery Chastain. After losing control of his car in a snow storm, Sheldon is rescued from the wreck by Annie Wilkes, a nurse who lives alone in Colorado. Wilkes is Sheldon's biggest fan, but also a disturbed and sadistic woman who keeps him hostage and forces him to continue writing. Subjected to unspeakable physical abuse, Sheldon eventually manages to kill Wilkes and escape, though not without being maimed in the process.
Paul Sheldon is the author of a best-selling series of Victorian era romance novels surrounding the character Misery Chastain. He has just finished the manuscript of his new crime novel, Fast Cars , while staying at the Hotel Boulderado. Since 1974, he has completed the first draft of every one of his novels in the same hotel room in Colorado. With his latest project finished, he has an alcohol-induced impulse to drive to Los Angeles rather than fly back home to New York City. However, a snowstorm hits while he is driving through the mountains. Sheldon drives off a cliff and crashes upside down into a snowbank.
Paul is rescued from the car wreck, which has resulted in shattered legs, by Annie Wilkes, a former nurse who lives nearby in the fictive town "Sidewinder" in Colorado. She takes him to her own home rather than a hospital, putting him in the guest bedroom. Using her nursing skills and stockpiled food and medical supplies, including an illicit stash of codeine-based painkillers, Annie slowly nurses Paul back to "health". Instead of setting his legs, as a doctor would have done (so that they may mend and eventually work), she puts them in makeshift splints. This results in his legs looking somewhat like a child's doodle. She proclaims herself as Paul's "number one fan," being an avid reader of the Misery Chastain series. However, when she reads the manuscript for Fast Cars , Annie argues with Paul on its violent content and profanity, causing her to spill his soup. Saying that the accident was "his" fault, she punishes him by withholding his medication, then forcing him to wash it down with soap water. Paul, who has done extensive research into mental disorders, suspects that Annie is dangerously disturbed.
Prior to the accident, when Sheldon's latest novel, Misery's Child , had hit the shelves, Annie had bought herself a reserved copy. She does not know, however, that Paul has killed Misery Chastain off at the end, intending to end the Misery series and re-establish himself as a mainstream writer. Upon learning of the main character's demise (which she reads while Sheldon is her captive), Annie rages at Paul before leaving him alone in her house without food, water or the painkillers for over two days lest he do something "unwise". During this time, Paul suffers from extreme pain and withdrawal symptoms due to the painkillers; by the time Annie returns, he is close to becoming comatose or dying. Annie forces him to burn the manuscript of Fast Cars – the book he hoped would launch his post-Misery career – and presents him with an antique Royal typewriter, for the purpose of writing a new Misery Chastain novel that will bring the character back from the dead.
Paul bides his time and writes the book as Annie wants, believing her fully capable of killing him. He manages to escape his room while Annie is on an errand, touring the house in search of more painkillers. He manages to reach her telephone as well, only to discover it to be "for show". He is almost caught by Annie, but manages to return to his room before she enters the house. On another occasion when Annie is absent, Paul escapes his room again and steals a knife from her kitchen, intending to kill her. On the way back to his room, he finds a scrapbook full of newspaper clippings from Annie's life, suggesting that she is a serial killer who murdered her own father, her college roommate, and numerous patients in several states– thirty-nine people in all. She was arrested and charged with killing several babies at a Boulder hospital, but was acquitted. He also finds a magazine clipping about his status as a missing person, the latest entry in the scrapbook.
Annie (who is prone to blanking out for gradually increasing durations of time, moodswings, depression where she slaps herself continuously, periods of time where she binges on food and sweets without using cutlery, mounting paranoia) eventually reveals that she knows about Paul's excursions from his room, and punishes him by cutting off Paul's foot with an axe (hobbling). Later, when Paul complains about a missing letter on the typewriter, she punishes him by slicing off his thumb with an electric knife. A Colorado state trooper eventually arrives at Annie’s house in search of Paul. Realizing a chance for escape, Paul alerts the officer by throwing an ash tray through the window, alerting him. However, Annie surprises the trooper, stabs him with a wooden cross and finishes him off with her lawnmower. She intends to kill Paul and herself to avoid being prosecuted for the crime, but Paul convinces her not to proceed by promising to write the novel. She temporarily hides Paul in the basement while she departs, meaning to dispose of the trooper's police cruiser.
Paul finally finishes writing Misery's Return and calls Annie, who has been eager to read it, to his room. He is aware that once Annie has read the completed book she intends on killing both of them, as the police are getting ever closer to discovering she killed the state trooper. Paul surprises Annie by using the single match she provided him with to light his cigarette (having convinced her that smoking was his normal practice after finishing a novel) to seemingly light his manuscript on fire in front of her—having first soaked it with a bottle of charcoal lighter fluid he smuggled to his room from the basement. While Annie frantically tries to put out the flames, which by this point have spread to her clothing, Paul lifts the heavy typewriter and throws it down hard onto Annie's back. The two engagein a violent struggle, with Paul stuffing Annie's mouth full of the burning pages. Annie gets to her feet and steps forward to attack Paul but trips on the typewriter, causing her to hit her head on the mantelpiece. Although first appearing to be dead, Annie awakens and crawls towards Paul who, inturn, frantically crawls away from Annie towards the door. Just as he reaches the threshold of the room, Annie reaches Paul and tries to strangle him, but instead she collapses from her injuries. Paul then crawls out of the room, closes the door, and locks the bolt that Annie had installed. After slumping down in front of the door, Paul feels Annie's fingers tugging his shirt from under it. Horrified at the question of how she is still alive, he pounds at her fingers then makes his way to the bathroom for more Novril. He finds and swallows some and sleeps against the door.
Awakening, Paul musters up the courage to leave the bathroom in an attempt to escape, uncertain if Annie is either alive or dead. After slowly crawling to the parlor, he sees headlights through a window and two state policemen approach the house. He finds an ornament of Annie's and throws it through the window to get their attention. When they find him, Paul warns them about Annie still being alive and her being locked in the guest bedroom. They leave him to investigate. When they return, they tell Paul that they had not found anything but a shattered bottle of champagne and the room burned. Paul screams until he faints. Later it is revealed that Annie had escaped through the window and gone out to the barn in order to get a chainsaw to kill Paul. However, she had died in the barn due to the skull fracture inflicted when she fell against the mantelpiece, one hand grasping the handle of the chainsaw.
Returning home to New York, Paul submits Misery's Return to his publisher (it was earlier revealed that he burned a decoy of the manuscript instead of the book itself). Paul's publisher tells him that the book will become his greatest bestseller, and wants him to write a nonfiction book about his ordeal. However, the ordeal is far from over for Paul: he suffers nightmares about Annie and continues to have withdrawals from painkillers. He has also become an alcoholic with writer's block. Eventually, after a random encounter with a child pushing a shopping cart containing a skunk in a cage, Paul has the same spark that inspired him to write Fast Cars and begins typing about this boy and his skunk, weeping as he types, both in misery for his shattered life and in joy that he is finally able to write again.