Quelques mois après Hôtel Transylvanie 2, tous les membres de la famille de Dracula et ses amis se réunissent pour partir en vacances à bord d'un luxueux bateau de croisière. Pendant la croisière, Dracula tombe amoureux du capitaine qui n'est autre que la descendante du professeur Van Helsing, le tristement célèbre tueur de monstres.
A short time after the first film, Mavis (Selena Gomez) and her fiance Johnny (Andy Samberg) are married, with the approval of her father Dracula (Adam Sandler) and the world has become aware of (and unfased by) the existence of monsters. Mavis later reveals to Drac that she is pregnant and a year later, she gives birth to a son named Dennis (Asher Blinkoff), who befriends Wayne's werewolf pup daughter Winnie (Sadie Sandler). Nearing his fifth birthday, Dennis has yet to grow his fangs and Drac worries that his grandson might not gain vampire powers. Noticing the dangers of Transylvania, Mavis starts to consider raising Dennis where Johnny grew up, much to Drac's disapproval.
In the aftermath of the death of Dracula's wife Martha (Jackie Sandler) at the hands of an angry mob, Count Dracula (Adam Sandler) designs and builds a massive five-star hotel in Transylvania in which to raise his daughter Mavis (Selena Gomez) and to serve as a getaway for all the world's monsters.
In 1887, Transylvanian Doctor Victor Frankenstein brings to life his Monster with the aid of his assistant Igor and Count Dracula. After Dracula betrays and kills Doctor Frankenstein, the Monster escapes to a windmill, which is burned down by a pursuing mob. The mob flees as Dracula and his three brides mourn the loss of the Monster.
"I busied myself to think of a story which would speak to the mysterious fears of our nature and awaken thrilling horror; one to make the reader dread to look around, to curdle the blood, and quicken the beatings of the heart."
In 1794, Captain Walton leads a daring, but troubled, expedition to reach the North Pole. While their ship is trapped in the ice of the Arctic Sea, Walton and his crew discover a man traveling across the Arctic on his own. The man reveals that his name is Victor Frankenstein and begins his tale.
Dr. Frederick Frankenstein (Gene Wilder) is a physician lecturer at an American medical school and engaged to the tightly wound socialite Elizabeth (Madeline Kahn). He becomes exasperated when anyone brings up the subject of his grandfather, the infamous mad scientist. To disassociate himself from his forebear, Frederick insists that his surname is pronounced "Fronkensteen."
Young filmmaker and scientist Victor Frankenstein lives with his parents, Edward and Susan Frankenstein, 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, mischievous, Igor-like Edgar "E" Gore, obese and gullible Bob, overconfident Toshiaki, 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.
In 1795, Dr. Victor Frankenstein (Aden Young) creates a monster (Aaron Eckhart), a soulless creature patched together from corpses, and then rejects it, disgusted with what he's made. In a fit of rage, the creature kills Victor's wife Elizabeth (Virginie Le Brun) and Victor chases it to the Arctic to get revenge, but succumbs to the weather. The creature buries his creator in the Frankenstein family crypt and is then attacked by demons before being rescued by the gargoyles Ophir (Mahesh Jadu) and Keziah (Caitlin Stasey), who bring it before the gargoyle queen Leonore (Miranda Otto) and their commander Gideon (Jai Courtney). Leonore explains that they were created by the Archangel Michael to battle demons on Earth and protect humanity. They name the creature "Adam" and invite him to join them, but he declines and departs after being given heavy, baton-like weapons to protect him, as more demons will come after him. The weapons allow him to "descend" demons (destroying their bodies and trapping their souls in Hell) as they have the symbol of the Gargoyle Order carved on them.
Told from Igor's perspective, it shows the troubled young assistant's dark origins, his redemptive friendship with the young medical student Victor Frankenstein, and become eyewitnesses to the emergence of how Frankenstein became the man who created the legend we know today. The two's experiments eventually get them into trouble with the authorities and they are near to becoming fugitives as they complete their goals to use science to create life, with Frankenstein's ultimate endgame of creating a man.
The Kingdom of Malaria's environment is devastated by a mysterious storm. Its king, Malbert, then blackmails the rest of the world to pay the town not to unleash the various doomsday devices invented by its Evil Scientists. They in turn are assisted by Igors, while the kingdom's annual Evil Science Fair showcases the scientists' latest weapons. One Igor, however, who serves the somewhat tedious-minded Doctor Glickenstein, is a talented inventor who aspires to be an Evil Scientist himself. Among his inventions are his friends "Scamper," a re-animated, immortal rabbit with a death wish and "Brain," a unintelligent human brain transplanted into a life support jar.
In a European village Henry Frankenstein, a young scientist, and his assistant Fritz, a hunchback, piece together a human body, the parts of which have been collected from various sources. Frankenstein desires to create human life through electrical devices which he has perfected.
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.
Jack Harrison (Goldblum) and Gil Turner (Begley) are writers for The Sensation, a supermarket-grade tabloid run by Turner's father, Mac (Norman Fell). Jack is a more serious journalist using The Sensation as a stepping stone to a better career, while Gil is a gangling yes-man ever ready to win his father's approval.