Seeking a legendary fortune in jewels, troublesome Collins family handyman Willie Loomis opens a hidden coffin in the Collins family crypt, releasing vampire Barnabas Collins from his 150-year confinement. Barnabas makes Willie his slave, then presents himself to the modern day Collins family (Roger, Elizabeth, Carolyn, and David) as a “cousin from England.” Barnabas moves into the “Old House” on the Collins estate, where the “first” Barnabas had lived. To thank his gracious hosts, Barnabas throws an elaborate costume ball.
Barnabas becomes attracted to the family governess Maggie Evans, who looks just like his long-lost love, Josette. When Carolyn, who has become one of the vampire’s victims, threatens to reveal his secret out of jealousy, Barnabas kills her. Carolyn rises from the grave as one of the undead, and seeks out her former lover, Todd Jennings. Professor T. Eliot Stokes uses the young man as bait for Carolyn, who is eventually trapped and staked by Stokes, aided by the Collinsport police.
Meanwhile, a doctor, Julia Hoffman, has studied blood samples from the victims and begins to conclude that vampirism is real and that it may be a curable disease. She has accidentally discovered, while using a compact mirror, that Barnabas is the vampire. She makes a pact with Barnabas and develops a serum to cure him.
The cure works for a while, and Barnabas’s courtship of Maggie proceeds. He gets her boyfriend, artist Jeff Clark, out of the way by arranging a showing of the young man’s paintings in nearby Boston. However, Julia, who has fallen in love with Barnabas, discovers his dalliance with Maggie. Insanely jealous, Julia gives Barnabas an overdose of the serum, with the result that he ages to his true 175 years. Barnabas angrily kills Julia, and restores his youth (and vampiric nature) by biting Maggie. He flees with the young woman. Stokes and Roger Collins quickly research the family history of Barnabas in 1797, and Stokes is convinced that Barnabas intends to take Maggie as his bride.
The search extends to St. Eustace, an island off the shore of Maine. Jeff discovers that both Stokes and Roger Collins have become vampires, and he has to destroy them both—Stokes with the silver bullets intended for Barnabas, and an arrow through the heart for Roger.
Jeff tracks the vampire to an abandoned monastery, where Barnabas is planning to make Maggie his bride. Jeff attempts to shoot Barnabas with a crossbow, but Willie, who is also infatuated with Maggie, rushes over to the altar to stop Barnabas. The arrow that Jeff aims at the obsessed vampire hits Willie in the back. Barnabas takes Jeff under his hypnotic control and is about to vampirize Maggie, when Willie revives and plunges the wooden shaft into Barnabas’s back, and then dies. Coming to his senses, Jeff finishes off Barnabas with the stake, which bursts through Barnabas’ chest; with Barnabas finally dead, Jeff leaves with the revived Maggie.
In the after credits scene, the seemingly dead Barnabas turns into a bat and flies away.