The novel is preceded by the prequel "Jerusalem's Lot," and followed by the sequel "One for the Road," both included in King's 1978 short-story collection Night Shift and in the 2005 illustrated edition of the novel.
Ben Mears, a successful writer who grew up in the town of Jerusalem's Lot, Maine, has returned home after twenty-five years. Once in town he meets local high school teacher Matt Burke and strikes up a romantic relationship with Susan Norton, a young college graduate.
Ben starts writing a book about the Marsten House, an abandoned mansion where he had a bad experience as a child. Mears learns that the Marsten House -- the former home of Depression-era hitman Hubert "Hubie" Marsten -- has been purchased by Kurt Barlow, an Austrian immigrant who has arrived in the Lot to ostensibly open an antique store. Barlow is an apparent recluse; only his familiar, Richard Straker, is seen in public.
The duo's arrival coincides with the disappearance of a young boy, Ralphie Glick, and the death of his brother Danny, who becomes the town's first vampire, infecting such locals as Mike Ryerson, Randy McDougall, Jack Griffen, and Danny's own mother, Marjorie Glick. Danny fails, however, to infect Mark Petrie, who resists him successfully. Over the course of several weeks almost all of the townspeople are infected.
Ben Mears and Susan are joined by Matt Burke and his doctor, Jimmy Cody, along with young Mark Petrie and the local priest, Father Callahan, in an effort to fight the spread of the vampires, whose numbers increase as the new vampires infect their own families and others. Susan is captured by Barlow before Mark has a chance to rescue her. Susan becomes a vampire, but is eventually staked through the heart by Mears, the man who loved her.
Father Callahan is caught by Barlow at the Petrie house after Barlow kills Mark's parents, but does not infect them, so they are later given a clean burial. Barlow holds Mark hostage, but Father Callahan has the upper hand, securing Mark's release, agreeing to Barlow's demand that he toss aside his cross and face him on equal terms. However he delays throwing the cross aside and the once powerful religious symbol loses its strength until Barlow can not only approach Callahan but break the cross, now nothing more than two small pieces of plaster, into bits. Barlow says "Sad to see a man's faith fail him", then forces the helpless Callahan to drink blood from Barlow's neck. Callahan resists but cannot hold out forever and is forced to drink, leaving him trapped in a netherworld, as Barlow has left his mark. When Callahan tries to re-enter his church he receives an electric shock, preventing him from going inside. Callahan disappears forever from "the Lot".
Jimmy Cody is killed when he falls from a rigged staircase and is impaled by knives by the one-time denizens of Eva Miller's boarding house, Mears' one-time residence, who have now all become vampires. Matt Burke dies from a heart attack in the town hospital. Ben Mears and Mark Petrie succeed in destroying the master vampire Barlow, but are lucky to escape with their lives and are forced to leave the town to the now leaderless vampires.
The novel's prologue, which is set shortly after the end of the story proper, describes the men's flight across the country to a seaside town in Mexico, where they stop to recover from their ordeal. Mark Petrie is received into the Catholic Church by a friendly local priest.
The epilogue has the two returning to the town a year later, intending to renew the battle. Ben, knowing that there are too many hiding places for the town's vampires, sets the town on fire with the intent of destroying it and the Marsten House once and for all.
The audiobook of 'Salem's Lot is read by Ron McLarty, a prominent audiobook reader.