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.
The following morning begins with the class and the new teachers taking ballet lessons. Gym class soon starts, to train the girls for their upcoming volleyball match against the boys of the neighboring Calloway Military Academy. The boys rig the volleyball with a remote control, but because of an accidental squirt of ketchup, the boys lose the remote, Scooby accidentally swallows the remote and it allows the girls to win instead.
The girls' fathers come for Open House, but as they leave, they warn Shaggy and Scooby not to let any harm come to their daughters or they'll be in big trouble. As an additional plot twist, Revolta, the self-styled Witch of the Web, and her minion, the Grim Creeper, plan to kidnap the girls and make them her slaves, by hypnotizing Shaggy into taking the girls on a field trip to the Barren Bog. That same day the Calloway Cadets are at the bog. With the help of Revolta's spider bats, Revolta and the Grim Creeper capture the girls and Revolta makes a potion that will make them evil forever at the stroke of midnight. Scooby, Scrappy, Shaggy, and Matches, along with the Calloway cadets manage to save the girls; and Revolta's plan is foiled.
Despite being well liked by all their students, Shaggy and Scooby have enough of this and run away when monsters such as an alien, the Creature from the Black Lagoon, and Godzilla enroll their daughters at the school for the following year screaming "Like, meet us in St. Louis". As they leave, they see the girls and Matches wave them goodbye. Shaggy, Scooby, and Scrappy then give them a last werewolf howl before driving off into the night.