A disheveled man in a suit (Ritch) wanders uncertainly down the main street of the small, rural town of Mountaincrest on a winter's night. Looking out of place and confused, he goes into a bar, where he tells the bartender that he doesn't know who or where he is. As he leaves, local thug Joe Mitchell (Charles Horvath) follows and demands his money. As the two men struggle in an alleyway, Ma Everett (Jean Harvey), who is passing, stops. She sees only four legs sticking out onto the sidewalk during the fight, but hears an animal snarling. Then two of the legs suddenly go limp. Someone — or something — steps out of the alley and looks Ma in the face. She screams in terror and it runs off into the darkness.
Sheriff Jack Haines (Megowan) takes Joe's body to Dr. Jonas Gilchrist (Ken Christy) and nurse Amy Standish (Holden). Gilchrist notes that the wounds look as if they were inflicted by a wild animal, but Ma described not an animal but "a thing." Jack organizes a posse to find the creature.
Later that night, Jack brings Deputy Ben Clovey (Harry Lauter) to Gilchrist's office with severe arm lacerations. Ben has been attacked by "the thing." He describes it haltingly to Jack: "Maybe it had hands covered with hair ... or maybe it had paws like a wolf ... but it wasn't all wolf ... I didn't have much time to see". Jack declares that Ben was attacked by a werewolf. After Jack and Ben leave, Gilchrist and Amy discuss Ben's and Joe's injuries and conclude that Jack is correct.
The disheveled man arrives at Gilchrist's medical office. All he can recall is having been taken to two doctors - he doesn't know who or where they are - after an automobile accident. He's tormented by what's happening to him, although he doesn't explain what that is. The man says he killed Joe. But he flees in fear when Amy attempts to give him a sedative, exclaiming, "Those other doctors did something to me!" After he runs off, Amy phones the sheriff.
The posse begins a more extensive manhunt. At about the same time, the two doctors, Morgan Chambers (George Lynn) and Emery Forrest (S. John Launer), discuss the man they'd treated after his car crash. They had injected him with "irradiated wolf serum", which they had never before used on humans. The doctors believe that the serum, when perfected, will allow "a select minority of people" — chosen by them — to survive the unavoidable nuclear holocaust that's coming. Lycanthropy, however, is an unfortunate side effect. But then Helen Marsh (Eleanor Tanin), the amnesiac man's wife, and their preteen son Chris (Kim Charney), show up at the doctor's laboratory. She identifies the man as Duncan Marsh. The doctors head to Mountaincrest, hoping to avoid blame by killing Duncan the werewolf themselves.
Chambers and Forrest search for Duncan. Forrest corners Duncan in a mineshaft. Looking at his rifle, Duncan pleads, "You're going to shoot me? Why? What have I ever done to you?" He suddenly transforms into the werewolf and attacks Forrest, but is driven off by shots fired by Chambers.
Helen and Chris also drive to Mountaincrest. After talking with them, Amy convinces Jack to try to take Duncan alive, and volunteers to help with first aid, as Duncan had been injured when he stepped into a bear trap laid for him when he was a werewolf. Helen says that she and Chris also want to go along. Jack reluctantly agrees and they, accompanied by Ben, set out to find Duncan.
Helen uses Jack's megaphone to call Duncan. Human again, he comes out of hiding and tearfully embraces Helen and Chris, but tells Amy to take them away as he fears he might turn into a werewolf again and harm them.
They put Duncan in a jail cell. Chambers and Forrest gain entry to the jail under false pretenses, render Ben and another deputy (Don C. Hardy) unconscious, and try to inject Duncan with something deadly. But Duncan has unexpectedly changed into a werewolf. He kills them both and again escapes into the woods.
The posse and the werewolf inevitably meet. Trapped on a bridge, the werewolf makes a desperate attempt to flee, but is shot dead by members of the posse. As the werewolf dies, it reverts to being Duncan again.
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