Driving through the Nevada desert, young couple Peter and Mary Jackson are stopped by local sheriff Collie Entragian. After discovering they possess marijuana (though it's implied Entragian planted it), he takes them to the police station in the nearby mining town of Desperation. Upon entering the police station, they see a little girl dead on the floor. Entragian shoots and kills Peter, then throws Mary in a jail cell along with a young boy, David Carver, his parents, Ralph and Ellen, and an old man, Tom Billingsley. The little girl is the Carver's daughter, named Pie. After Entragian leaves, David kneels and prays to God, his practice since a drunk driver struck his best friend, Brian.

Meanwhile, Steve Ames is in his truck, following famous author Johnny Marinville, for whom he is currently working as an assistant. Steve soon picks up a young female hitchhiker named Cynthia Smith. Johnny stops in the desert to urinate just as Entragian shows up behind him. Entragian initially declares himself a huge fan, but after planting and discovering the same bag of marijuana he got from Peter and Mary in Johnny's motorcycle bag, he brutally beats and arrests Johnny as well.

Back in the police station, Ellen asks David why he continues to pray. David reveals that he prays because he believes God made "His" presence known to him by saving his friend Brian from the brink of death. He explains that a drunk driver hit Brian when he and Brian were riding a bike. David immediately began praying to God, offering to do whatever was asked of him so that his friend be saved. At that point, Brian regained consciousness, the doctor at the hospital describing his recovery as "miraculous."

When Entragian returns to the station with Johnny, David notices Entragian's skin is cracked and decayed, and he is repeatedly uttering the word "Tak". Entragian then takes Ellen from her cell at gunpoint and departs again, leaving a desert coyote (over which he seems to exert an unnatural amount of control) to guard the cells. Pie's ghost appears and gives David a bar of soap, which David uses to scrub his body and, while the coyote is distracted, slips through the bars of the jail cell and escapes the holding area. David searches the police station and finds a gun on the corpse of another sheriff. He returns and shoots the coyote, freeing everyone.

Meanwhile, Steve and Cynthia catch up to where Entragian captured Johnny. He and Cynthia find Johnny's motorcycle hidden within some dry bushes. After arriving in Desperation, they search the town, finding all the residents dead. They soon encounter Entragian's escaped prisoners. The group gather at a disused theater, and Tom tells a story that took place 120 years ago when Chinese workers digging in a local mine known as 'The China Pit' discovered an evil, long-dormant subterranean spirit named "Tak."

Entragian, whose body is now on the verge of falling apart entirely, drives Ellen to the China Pit. There, the spirit of Tak switches from Entragian's body into Ellen's. The now-possessed Ellen returns to the station to find the prisoners gone. Enraged, she tracks them to the theater, and sends in a mountain lion which attacks and kills Tom. Tak then captures Mary as a replacement for when Ellen's body inevitably decays from the corrosive evil of the spirit possessing it.

David sees Pie's ghost in the theater again. She leads him to the movie editing machine, where he experiences a vision (seen through old footage) revealing the release of Tak from the old mine. Mary wakes up to find herself trapped in a shed, surrounded by rattlesnakes, scorpions, and tarantulas, waiting to be Tak's next host. With the help of Pie, she manages to escape the shed and fight her way out of Tak's grasp, damaging Ellen's body in the process. Tak is forced to possess a buzzard.

Johnny confesses that 40 years ago in Vietnam, he saw a man detonate an explosive in the bathroom of a bar, killing 87 people. Johnny still feels guilty that he did not warn any of the patrons before fleeing the bar. The group locates some mining explosives and decides to return to the mine and attempt to put an end to Tak. At the entrance, the buzzard attacks and kills Ralph. Hoping for some form of redemption, Johnny enters the mine and descends into the pit where Tak resides. Johnny ignites the explosives, destroying the mine and himself, while the rest of the survivors leave in Steve's truck.

While driving away from the town, they pass the empty RV owned by David's family and Peter's sister's car. Mary tells Steve to stop the truck to retrieve an overnight case from the car. In the back seat, Mary finds a photo album belonging to David with a frontispiece picture of Johnny and Pie together, which Steve identifies as being signed by Johnny.

• Tom Skerritt as Johnny Marinville, a famous author who was in Vietnam when he was young
  • Tom Parker as Young Johnny
• Ron Perlman as Collie Entragian, the sheriff of the town of Desperation, already possessed by Tak at the start of the movie
• Steven Weber as Steve Ames, a man who works for Johnny
• Annabeth Gish as Mary Jackson, Peter's wife
• Charles Durning as Tom Billingsley, an old veterinarian who lives in the town
• Shane Haboucha as David Carver, a boy who talks to God
• Matt Frewer as Ralph Carver, David's father
• Kelly Overton as Cynthia Smith, female hitchhiker
• Henry Thomas as Peter Jackson, Mary's husband
• Sylvia Kelegian as Ellen Carver, David's mother
• Sammi Hanratty as Pie Carver, David's deceased sister
• Ewan Chung as Shih, Chinese miner, brother to Cha'an
• Alain Uy as Cha'an, Chinese miner, brother to Shih
• Trieu Tran as Young Viet Cong

The film was produced in 2004, though it was not released until 2006. Filming primarily took place in Bisbee, Arizona, in the nearly deserted Lowell borough, with other sequences in Old Bisbee, the outskirts of Bisbee and Tucson, Arizona. During filming, a set in the Tucson Convention Center (TCC) caught fire. Five people were injured. The fire destroyed everything on the set, including all production gear and equipment, and the TCC was heavily damaged.^{[citation needed]}

The film was first broadcast in the United States on May 23, 2006, followed by its DVD release in the United States on August 29 of the same year.^{[citation needed]} The film received moderately favourable reviews, including a 46 rating from Metacritic.^[2] Though originally intended as a two-part miniseries, Desperation aired in its entirety on May 23, 2006, on ABC, after a red-carpet premiere screening at Tucson's historic Fox Theatre (built in 1929). ABC aired Desperation at the same time as Fox's American Idol, an action that King himself was upset with,^[3] believing it did not do as well in the ratings because of that

• Stephen King's Desperation at IMDb