Young filmmaker and scientist Victor Frankenstein (Charlie Tahan) lives with his parents, Edward (Martin Short) and Susan Frankenstein (Catherine O’Hara), and his beloved dog, Sparky, in the quiet town of New Holland. Victor’s intelligence is recognized by his classmates at school, his somber next-door neighbor, Elsa Van Helsing (Winona Ryder), mischievous, Igor-like Edgar “E” Gore (Atticus Shaffer), obese and gullible Bob (Robert Capron), overconfident Toshiaki (James Hiroyuki Liao), creepy Nassor, and an eccentric girl nicknamed Weird Girl, but communicates little with them due to his relationship with his dog. Concerned with his son’s isolation, Victor’s father encourages him to take up baseball and make achievements outside of science. Victor hits a home run at his first game, but Sparky, pursuing the ball, is struck by a car and killed.
Inspired by his science teacher Mr. Rzykruski’s (Martin Landau) demonstration of the effect of electricity on dead frogs, a depressed Victor digs up Sparky’s corpse, brings him to his makeshift laboratory in the attic and successfully reanimates him with lightning. Seeing Weird Girl’s living cat, Mr. Whiskers, the undead Sparky escapes from the attic and explores the neighborhood. He is recognized by Edgar, who blackmails Victor into teaching him how to raise the dead. The two reanimate a dead goldfish, which turns invisible due to an error with the experiment. Edgar brags about the undead fish to Toshiaki and Bob, which, in panic of losing the upcoming science fair, inspires them to make a rocket out of soda bottles, which causes Bob to break his arm and Mr. Rzykruski to be blamed and fired due to his accused influencing and reviling the townsfolk for questioning his methods when he steps up for self-defense. So, the gym teacher replaces Mr. Rzykruski.
Eventually, Edgar’s fish disappears when he tries to show it to a skeptical Nassor (who was told by Toshiaki), and when Edgar is confronted by Toshiaki, Nassor and Bob on the baseball field at school, he accidentally reveals Victor’s actions, inspiring them to try reanimation themselves. Victor’s parents discover Sparky in the attic and are frightened, causing the dog to flee. Victor and his parents search for Sparky while the classmates invade the lab, discovering Victor’s reanimation formula. The classmates separately perform their experiments, which go awry and turn the dead animals into monsters — Mr. Whiskers holds a dead bat while it is electrocuted, resulting in him fusing with it and becoming a monstrous bat-cat with wings and fangs. Edgar turns a dead rat he found in the garbage into a wererat, Nassor revives his mummified hamster Colossus and Toshiaki’s turtle Shelley is covered in Miracle Gro and turns into a giant Gamera-like monster. Bob’s Sea-Monkeys grow into amphibious humanoids. The monsters break loose into the town fair where they wreak havoc.
After finding Sparky at the town’s pet cemetery, Victor sees the monsters heading to the fair and goes with his classmates to help deal with them — the Sea-Monkeys explode after eating salt-covered popcorn, and Colossus is stepped on by Shelley, while the rat and Shelley are returned to their original, deceased forms after both being electrocuted. During the chaos, Persephone, Elsa’s pet poodle, is grabbed by Mr. Whiskers and carried to the town windmill with Elsa and Victor chasing after. The townsfolk blame Sparky for Elsa’s disappearance and chase him to the windmill, which Mayor Burgermeister accidentally ignites with his torch. Victor and Sparky enter the burning windmill and rescue Elsa and Persephone, but Victor is trapped inside. Sparky rescues Victor, only to be dragged back inside by Mr. Whiskers. A final confrontation ensues, and just as Mr. Whiskers has Sparky cornered, a flaming piece of wood breaks off and impales the bat-cat, killing him instantly. The windmill then collapses on Sparky, killing him again. To reward him for his bravery and saving Victor, the townsfolk gather to revive Sparky with their car batteries, reanimating him once more. Persephone, who has a hairstyle similar to Elsa Lanchester’s Bride of Frankenstein, comes to Sparky as the two dogs share their love and kiss.