The film begins with the groaning of a woman. The camera slowly pans to show two elderly women (who look like twins) and an elderly man who are watching a woman writhe and moan with the pain of childbirth on a bed in an old-fashioned looking bedroom. She is then led out of the room by the elderly man, who is later revealed as the elder Whateley.
Susannah Kelton, a newly married twentysomething who was raised in foster care in the big city, learns that her real parents have only recently died and left all of their property to her. She and her husband, Mike, travel to the island of Dunwich off the coast of Massachusetts to inspect the property. They find a local culture that is clannish, backward and ignorant. The few friends they make amongst the locals, including Susannah's Aunt Agatha, warn them that the family mill is cursed and urge the Keltons to leave immediately and never look back. Refusing to bow to superstition, the Keltons consider rehabilitating the abandoned mill. They become the target of a gang of local thugs led by Susannah's lecherous cousin, Ethan. Their reign of terror is ended by something still living in the shuttered attic room of the mill, something that caused Susannah nightmares as a child.
Stephen Reinhart, an American scientist (Nick Adams), pays a visit to the estate of his British fiancée's family. He finds a scorched area of countryside near an enormous crater. Local townspeople are hostile toward him and refuse to either drive him to his destination or talk about the family that lives there. The source of all these problems is later revealed to be a radioactive meteorite kept hidden in the basement by his girlfriend's father, Nahum Witley (Boris Karloff), who has been using the radiation to mutate plant and animal life, with horrific consequences to his subjects and to members of his family.
In 1765, the inhabitants of the town of Arkham are suspicious of the strange phenomena surrounding the grand "palace" that overlooks the town. They suspect its inhabitant, Joseph Curwen, of being a warlock.