'Salem's Lot is the story of writer Ben Mears and his return to the title location, his childhood home. Ben befriends local child Mark Petrie in the midst of an outbreak of vampirism begun by the arrival of the mysterious Austrian Kurt Barlow. Barlow is a master vampire who moves into the Marsden House, a haunted dwelling about which Ben hoped to write a novel. The town succumbs to the plague until Ben and Mark set fire to it and flee cross-country.
Ben Mears, a writer who spent part of his childhood in Jerusalem's Lot, Maine, has returned after twenty-five years. He quickly becomes friends with high school teacher Matt Burke and strikes up a passionate romantic relationship with Susan Norton, a young college graduate.
Ben starts writing a book about the Marsten House, an abandoned house 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 ostensibly to open a store. Barlow is on an extended buying trip; only his business partner, 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 by holding a plastic cross in Danny's face. Within several weeks many of the townspeople are turned into vampires.
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 new vampires. Susan is captured by Barlow and made into a vampire, eventually being staked through the heart by Mears, the man who loved her.
Mark's parents are killed next, but Barlow does not infect them, so they are later given a clean burial. Barlow holds Mark and Father Callahan 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", Callahan then has to drink blood from Barlow's neck. Callahan resists but is forced to drink, leaving him 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 never goes near another church again.
Jimmy Cody is killed when he falls from a rigged staircase and is impaled by knives set up by the one-time denizens of Eva Miller's boarding house, Mears' one-time residence, who have now all become vampires. 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 Ben and Mark's flight across the country to a seaside town in Mexico, where they attempt to recover from their ordeal. Mark is received into the Catholic Church by a friendly local priest and confesses for the first time what they have experienced.
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 vampires, deliberately starts a brush fire in the woods near the town with the intent of destroying it and the Marsten House once and for all.