Stephen King's 'Salem's Lot chronicles the return of writer Ben Mears to his childhood home in Jerusalem's Lot, Maine (abbreviated as ‘Salem’s Lot). Ben returns, after twenty-five years, to his seemingly sleepy childhood town to revisit the Marsten House, an abandoned old home where Ben had a traumatic childhood experience. At the house he saw a hanging ghost, and the apparition understandably startled him. He hopes this will provide inspiration for his forthcoming novel. While reconnecting with places and people from his past, Ben also strikes up a new relationship with Susan Norton, a recent graduate with plans to leave the town, and discovers that places from his past are not exactly as he left them. Most notably, the Marsten House has a new, mysterious, and currently absent owner, Kurt Barlow, who has recently arrived in town to open an antique store with his business partner, Richard Straker. Barlow is an Austrian immigrant who plans to open up a furniture store. In actuality, it becomes clear that Barlow is truly a vampire and Straker is his human familiar, or supernatural servant.

The sleepy, quiet town of 'Salem's Lot becomes a locus of commotion and concern soon after Barlow and Staker arrive. Two young brothers, Ralphie and Danny Glick, each fall victim to tragedy. First, Ralphie mysteriously disappears, and then Danny dies. With Danny's death, the central horror and mystery of King's novel begins to unfold. Though the circumstances of Danny's death are initially unknown, the townspeople soon discover that he has become a vampire. After Danny infects his first round of victims, which includes some of his classmates and family members, many of the citizens of 'Salem's Lot are transformed into vampires.

Spared in the first waves of infection, Ben and Susan assist with the effort to combat the takeover of vampires in their town. They join forces with Mark Petrie (the only one of Danny's victims to survive an attempted attack by Danny), Father Callahan, Matt Burke, and Dr. Jimmy Cody. Despite their noble efforts to thwart the vampires, most of these would-be protagonists and their loved ones meet their demise as they make the discovery that Kurt Barlow is the master vampire responsible for the current state of affairs in 'Salem's Lot. Barlow captures Susan and turns her into a vampire. She is ultimately put out of her misery by her lover, Ben, who stabs her with a stake through the heart. Father Callahan and Mark encounter Barlow in the Petrie family home, where Father Callahan's religious attempts to rebuke Barlow prove unsuccessful. Dr. Cody is murdered by the vampires.

Mark and Ben are able not only to elude Barlow but to defeat him as well. However, killing Barlow does not defeat the other vampires, whose ranks now include the entire town. Ben and Mark are forced to flee 'Salem's Lot.

Ben and Mark return to the town one year later after the main story itself has ended. They have plans to fight the vampires yet again. They are leaderless with the defeat of Barlow—they lack the organization and purpose they once held as Barlow’s underlings. This makes them less predictable. Ben is aware that there are far too many places in which the vampires of the town may be hiding; to even the playing field, he starts a brush fire in the woods close to ‘Salem’s Lot.