On the Isle of Evil, 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 (sometimes referred to as "Fang") and the Monster's more intelligent mate (voiced by Phyllis Diller) who live in the isle's 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 just "The Creature").
The Baron's beautiful assistant Francesca (voiced by Gale Garnett) enters the lab to confirm that all invitations have been delivered and inquires about one of the addressees named Felix Flanken (voiced by Allen Swift impersonating James Stewart). Frankenstein explains that Flanken is his nephew and successor in the monster business. This displeases Francesca, who covets the role for herself. Francesca even asks why there was not an invitation for "It". Boris replies that "It" was not invited since "It" can be a crushing bore, explaining that "It" even crushed the island's wild boars in his bare hands the last time "It" was invited.
Frankenstein has his zombie butler Yetch (Swift impersonating Peter Lorre), Chef Mafia Machiavelli, and the zombie bellhops and servants make preparations for the upcoming party while having some zombies patrol the Isle of Evil to make sure that "It" does not show up uninvited. The monsters begin to arrive on the freighter that Felix is also traveling on.
However, when Felix proves to be an incompetent, asthmatic (and unsuitably kind-hearted) human, the monsters plot to eliminate him and gain control of the secret formula. Over time, Francesca develops feelings for Felix after he unknowingly saves her multiple times. As Dracula, Frankenstein's Monster, and the Monster's Mate descend upon Francesca, she sends out a letter (via messenger bat) to an unknown recipient. When the monsters corner Felix upon capturing Francesca, they are frightened at the arrival of "It" (revealed to be a giant gorilla and a take-off of King Kong) who proceeds to go on a rampage since he was not invited. "It" snatches up the monsters and Francesca (on whom "It" develops a crush).
Felix rushes off to tell his Uncle Boris what happened and is instructed to head to the boat. Boris leads the zombies in rescuing Francesca from "It" using biplanes. Boris convinces "It" to let Francesca go and to take him instead. "It" complies, releasing Francesca. Felix and Francesca manage to get off the island as Boris and the remainder of the monsters remain in the clutches of "It". Displeased that the monsters tried to steal the secret of total destruction for themselves and attempted to kill Felix as well (in addition to having to put up with "It"), Boris sacrifices his life by dropping the vial containing the formula destroying the Isle of Evil and everything on it.
The destruction is witnessed offshore by Felix and Francesca. Francesca tearfully admits to Felix that she is not human, but is in fact a robot creation of Boris von Frankenstein. Felix answers that "none of us are perfect" (an in-joke reference to the closing line of the movie "Some Like It Hot"), mechanically repeating the last two words, indicating that he is also a robot creation of his uncle.
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