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Ben Mears returns to the town of Jerusalem's Lot in Maine, where he spent four years as a child twenty-five years earlier. He's working on a book about the creepy Marston House. (He is the hero because he's a writer from Maine, and writers from Maine are cool. Just ask a writer from Maine like Stephen King.) Ben meets Susan Norton, a recent college graduate and author who falls for him quick because this isn't a romance book, and the plot's got other things to do.
Meanwhile, Kurt Barlow, an immigrant, purchases the Marston House with help from his bald buddy Richard Straker. They claim they are opening an antique store, but in fact Barlow is a demonic creature of the night come to suck the townspeople's blood. Straker murders a little boy, Ralphie Glick, as a sacrifice to Barlow, who then turns Ralphie's brother, Danny, into the town's first vampire. Things go from worse to worse than that, with people dying left and right and vampires rising and the town sinking swiftly into degradation, filth, and large incisors.
Ben figures out what's happening because, hey, he's a writer and (all together now) writers know what's up. Joining up with him to fight the good fight are Susan, an English teacher named Matt Burke (did we mention that Stephen King worked as an English teacher, too?), Matt's doctor Jimmy Cody, the local Irish priest Father Callahan, and Mark Petrie, a smart, tough kid who likes horror films. Alone, they'd have no chance against the fearsome vampires, but together… well, it still doesn't seem like they have much chance.
And, in fact, things don't go super well for them. Matt has a minor heart attack after confronting a vampire in his house and ends up in the hospital. Susan's ex-boyfriend Floyd Tibbets is turned into a half-vampire by Barlow, and under his orders beats Ben up and puts him in the hospital, too.
Susan decides to confront Barlow in the Marston House on her own. She runs into Mark… and the two of them get captured almost immediately by Straker. Mark breaks free, bashing Straker in the head in the process, and leaving him all bloody so that Barlow can't resist and ends up eating him. Unfortunately, Mark isn't in time to free Susan, who is caught and turned into a vampire. This makes Ben sad, as you'd imagine. If only Susan had been a writer, she would have been too cool to get killed.
Acting under Matt's advice, Ben, Mark, Jimmy and Father Callahan go to the Marston House during the daytime. There, they find and stake Susan and seal the house off with the Host. Barlow leaves a letter threatening Mark's parents, so Callahan and Mark go to warn them. Before they can convince them to run, though, Barlow shows up and kills Mark's mom and dad, which makes Mark sad, as you'd imagine. Mark escapes under cover of Callahan's faith-powered cross, but then Callahan loses faith and Barlow makes him drink Barlow's vampire blood, which, besides being gross, marks him as damned. Callahan catches a bus out of town and feels sorry for himself, not necessarily in that order.
Barlow and the vampires trick Jimmy into a booby trap involving sawed off stairs and knives and lots of blood. Matt has a heart attack. So it's just Ben and Mark left. They track Barlow to his new daytime spot in Ben's boarding house, and, much to Barlow's surprise and indignation, they stake him, stake him good (to paraphrase Devo.) The other vampires are upset, but Ben and Mark have cleverly bathed in holy water, so they just walk out.
Ben and Mark travel for a while, getting all the way to Mexico (this part of the story is told in the novel's preface.) They'd hoped the vampires would go away or something after they staked Barlow. The logic isn't entirely clear—though, to be fair, you probably wouldn't be thinking clearly either if you'd just fought a town full of vampires.
Anyway, while reading news clippings, our heroes realize that nastiness is still going on back home. So they come back to the Lot a year later and set a fire to smoke out all the vampires so that they can stake them all. It seems like Ben and Mark are going to kill all the vampires, though King later wrote a story in which it turns out that this didn't quite happen (see "What's Up With the Ending?").