On October 30, 1977, amateur criminals Killer Karl and Richard Wick attempt an armed robbery at a gas station/horror museum, but are killed by the owner, Captain Spaulding, and his assistant, Ravelli. Later that night, Jerry Goldsmith, Bill Hudley, Mary Knowles, and Denise Willis are on the road in hopes of writing a book on offbeat roadside attractions. When the four meet Spaulding, who is also the owner of "The Museum of Monsters & Madmen", they learn of the local legend of Dr. Satan. As they take off in search of the tree from which Dr. Satan was hanged, they pick up a young free-spirited hitchhiker named Baby, who claims to live only a few miles away. Shortly after, a mysterious figure appears hidden in some overgrowth and shoots out their vehicle's tire with a shotgun. The group thinks it is just a blown out tire and so Baby takes Bill to her family's house to get a tow truck. Moments later, Baby's half-brother, Rufus, picks up the stranded passengers and takes them to the family home.
There they meet Baby's family: her adopted brother Otis Driftwood, her deformed giant half-brother Tiny, Mother Firefly, and Grandpa Hugo. While being treated to dinner, Mother Firefly explains that her ex-husband, Earl, had previously tried to burn Tiny alive, along with the Firefly house, after he suffered a psychotic breakdown. After dinner, the family puts on a Halloween show for their guests and Baby offends Mary by flirting with Bill. After Mary threatens Baby, Rufus tells them their car is repaired. As the couples leave, Otis and Tiny, disguised as scarecrows, attack them in the driveway and take them prisoner. The next day, Otis kills Bill and mutilates his body for art. Mary is tied up in a barn, Denise is tied to a bed while dressed up for Halloween, and Jerry is partially scalped for failing to guess Baby's favorite movie star.
When Denise doesn't come home, her father Don calls the police to report her missing. Two deputies, George Wydell and Steve Naish, find the couples' abandoned car in a field with a dead, mutilated cheerleader in the trunk (one of five cheerleaders who went missing over a week ago, as explained in a news broadcast). Don, a former policeman, is called to the scene to help the deputies search. They arrive at the Firefly house and Wydell questions Mother Firefly about the missing teens. Mother Firefly shoots Wydell in the head and kills him; Don and Steve are then killed by Otis when they find more bodies of missing cheerleaders in the barn, along with a barely conscious Mary.
Later that night, the three remaining teenagers are dressed as rabbits and taken out to an abandoned well. Otis torments Denise using the skin of her dead father's face as a mask. Mary attempts to run away, but is tracked down and stabbed to death by Baby moments later. Otis and the family burn the bodies on a pyre.
Meanwhile, Jerry and Denise are placed in a coffin and lowered into a well, where a group of Dr. Satan's failed experiments break open the coffin and pull Jerry away, leaving Denise to find her way through an underground lair. As she wanders through tunnels filled with mutilated corpses, she encounters Dr. Satan and a number of mental patients; Jerry is on Dr. Satan's operating table being vivisected, and dies as Denise screams. Dr. Satan orders his mutated gargantuan assistant, who turns out to be Mother Firefly's ex-husband Earl, to capture Denise, but Denise outwits him and escapes by crawling to the surface as Earl is crushed by falling debris in the collapsing tunnel.
She makes her way to the main road, where she encounters Captain Spaulding, who gives her a ride in his car. She passes out from exhaustion in the front seat, and Otis suddenly appears in the back seat with a knife. Denise later wakes up to find herself strapped to an operating table, surrounded by Dr. Satan and Earl, who survived the cave-in. The movie ends with Denise screaming in horror and the words "The End?" displayed before the end credits.
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