After a large crate is delivered to the Marsten House one night, an increasing number of the townsfolk begin to disappear or die in strange circumstances. Both Mears and Straker are initially the main suspects as they are new in town, but it becomes clear that the crate contained Straker's mysterious business partner, Kurt Barlow, an ancient master vampire who has come to the town after having sent Straker to make way for his arrival. Straker kidnaps a young local boy, Ralphie Glick, as an offering to Barlow, while Barlow himself kills local realtor Larry Crockett. The Glick boy then returns as a vampire to claim his brother, Danny, who himself becomes undead. In turn, Danny infects the local gravedigger, Mike Ryerson, who was entranced by the undead child's open eyes. Danny then attempts to prey on his schoolfriend Mark Petrie. However, Mark is a horror film buff who manages to repel Danny with a crucifix.
Slowly, the vampires spread as Mears, Burke, and Bill Norton figure out what is happening to the town and attempt to do something to stop it. They are attacked by the presumed dead Marjorie Glick (Ralph and Danny's mother) after she awakens on the mortician's table. Mark's parents are both killed by Barlow, though Mark is allowed to escape when the local priest, Father Callahan, holds him at bay. Jason Burke, however, falls prey to a heart attack following an encounter with the newly vampirised Mike Ryerson. In the end, Susan Norton and Mark Petrie are captured by Straker after breaking into the Marsten House. Mears and Dr. Norton head over to the house to destroy Barlow when they run into Mark who has managed to escape. Inside the house, Dr. Norton is killed by Straker, who is himself then killed by Mears using a pistol. Afterwards, Mears and Petrie find Barlow's coffin in the cellar and destroy him by driving a stake through his heart. They then escape from the other vampires in the cellar (the various townsfolk), and set fire to the house. However, Susan is nowhere to be found. As the house burns, the wind begins to carry the fire towards the town itself. Mears and Petrie then flee Salem's Lot knowing that the fire will drive all the other vampires from their hiding places and purify the town from the evil that has engulfed it.
The story then returns to Mears and Petrie at the church in Guatemala two years later. It quickly becomes clear that they are on the run from the surviving vampires from Salem's Lot, who have been relentlessly pursuing them. Their supplies of holy water glow whenever a vampire is nearby. Realising that they have been tracked down yet again, Mears and Petrie return to their lodgings to collect their belongings. However, once there, Mears finds Susan lying in his bed. Now a vampire, she prepares to bite him as he leans down to kiss her, but he drives a stake through her heart. Filled with grief, he and Petrie leave, knowing that vampires are still hunting them.