Moira Frankenstein (Lina Romay), la fille du défunt professeur, découvre la "déesse" (Michelle Bauer), une créature féminine créée par son père. Fascinée, elle n'a plus qu'une idée en tête : trouver de jeunes filles pour contenter la créature.
After Baron Henry von Frankenstein creates a bride his monster, he decides to make arrangements for a lavish wedding at the Transylvania Astoria Hotel. Many monsters are invited to the wedding including Count Dracula and his son, Ron Chanley the Werewolf, the Mummy, Dr. Jekyll and Mr. Hyde, the Invisible Man and his family, and the Creature from the Black Lagoon. Once the wedding guests arrive, they terrify guests and staff. Frankenstein's assistant Igor is jealous of the monster and wants the bride for his own. So Igor plots to steal her which doesn't go according to plan when the bride ends up snatched up by a Pterodactyl and lands in the clutches of a giant gorilla named Modzoola.
Baron Boris von Frankenstein (voiced by Boris Karloff) achieves his ultimate ambition, the secret of total destruction. Having perfected and tested the formula, he sends out messenger bats to summon all monsters to the Isle of Evil in the Caribbean Sea. The Baron intends to inform them of his discovery and also to reveal his imminent retirement as head of the "Worldwide Organization of Monsters". Besides Frankenstein's Monster (referred to as "Fang") and the Monster's more intelligent mate (voiced by Phyllis Diller) who live in the island castle with Boris, the invites also include Count Dracula, the Mummy, Quasimodo (referred to as "The Hunchback of Notre Dame"), the Werewolf, The Invisible Man, Dr. Jekyll and Mr. Hyde, and the Creature from the Black Lagoon (referred to as the "Creature").
A teenage couple, Mary and Scott, are on their way home from a Halloween party when car trouble prompts them to seek help at the old mansion of Dr. Frankenstein. Once inside, they meet a host of strange characters, at whose mercy Scott and Mary suddenly find themselves when Frankenstein informs them, "I'm sorry the bridge is out, you'll have to spend the night!"
The story opens in the 1950s, after the Korean War; it has been more than a decade since James Whale, director of Frankenstein and Bride of Frankenstein, has retired. He lives with his long-time housemaid, Hanna, who loyally cares for him but disapproves of his homosexuality. Whale has suffered a series of strokes that have left him fragile and tormented by memories: growing up as a poor outcast, his tragic World War I service, and the filming of The Bride of Frankenstein. Whale slips into his past, and indulges in his fantasies, reminiscing about gay pool parties and also sexually teasing an embarrassed, starstruck fan who comes to interview him. Whale battles depression, at times contemplating suicide, as he realizes his life, his attractiveness, and his health are slipping away.
Dr. Victor Frankenstein creates a monster to show his scientific theories, but soon leaves him. So the scientist tries to rebuild his live getting married with Janet, and retires to his castle with Igor. However the monster goes back to haunt Frankenstein, and so Victor finds out that the monster has ferocious sexual orientation to Janet. Frankenstein then calls the servant Igor to readjust the monster, but also Igor takes advantage of Janet...
Every year, all of the classic Hollywood monsters (consisting of Frankenstein's monster, his wife Repulsa, a Mummy, the Witch Sisters, Bone Jangles the Skeleton, Dr. Jekyll/Mr. Snyde, Swamp Thing, and Dragonfly) gather at Count Dracula's castle in Transylvania for the "Monster Road Rally", an ultimate road race similar to Wacky Races, awarding the winner with the "Monster of the Year" award as well as many other prizes only monsters would enjoy (and one prize — a trip to Hawaii — that none of the monsters want). This year, however, Dracula receives a postcard from the Wolfman stating that he has retired to Florida and will not be participating.
Velma gets a call from Cuthbert Crawley, a lawyer for Velma's family who tells her that she's inherited her great uncle's property and castle in Transylvania. Velma turns the offer down, replying she wants nothing to do with her uncle, puzzling the gang. Mr. Crawley understands, revealing the curse over the estate. He says that if anyone gets too close to the Baron legacy, then what they love the most will be destroyed. As they head outside, Fred hears a noise from the Mystery Machine, then it explodes and a mysterious character with a mask appears. Crawley reveals that it's the ghost of the Baron, Velma's old ancestor. The remains of the machine explode again, with words saying stay away from Transylvania, but Fred declares that is where they're going to find the person responsible for destroying the Mystery Machine, saying this time "it's personal".
Scooby-Doo, Shaggy, and Scrappy-Doo are on their way to a Miss Grimwood's Finishing School for Girls, where they have been hired as gym teachers. Once there, however, they find that it is actually a school for girl ghouls. The pupils include Sibella, the daughter of Count Dracula; Elsa Frankenteen, the daughter of Frankenstein's monster, Winnie, the daughter of The Wolfman; Phantasma (usually called Phanty for short), the daughter of a phantom, possibly The Phantom of the Opera; and Tanis, the daughter of The Mummy - all parodies/tributes to the Universal Monsters of the 1930s-40s. Other residents of the school are a floating white hand; an octopus, who is the school's butler; Legs, a spider that helps with the upcoming volleyball match; Miss Grimwood, the headmistress; and her pet dragon Matches (who dislikes Scooby at first, but later becomes friends, and has a strong friendship with Scrappy). Shaggy and Scooby want no part of this at first, but eventually they agree to stay as teachers.
After the killing of his father (Count Dracula, the King of the Netherworld), by a mysterious assassin, Count Downe (Harry Nilsson) is summoned from his travels abroad by family advisor Merlin (Ringo Starr) in order to prepare him to take over the throne. Baron Frankenstein (Freddie Jones) is also on hand to help in any way he can. Problem is, Downe wants no part of this responsibility, and instead wishes to become human and mortal − especially after meeting a girl named Amber (Suzanna Leigh), with whom he falls in love. He approaches old family nemesis Dr Van Helsing (Dennis Price), who agrees to enable the Count's transformation, much to the dismay of the residents of the Netherworld.
Stan Helsing (Steve Howey) is an underachieving employee at a video rental store named Schlockbuster whose personal mottos are "Don't get involved" and "Don't talk about it". His teen-aged boss Sully orders him to drop off a bag of movies to the mother of the store's owner or risk not having a job Monday morning. Despite his arguments, he agrees to the request and manages to get his friend Teddy (Kenan Thompson), his ex-girlfriend Nadine (Diora Baird) and ditsy blond massage therapist Mia (Desi Lydic) to take him there before they attend a Halloween party, even though it's on the other side of town.