During the joyful festivities marking the 125th anniversary of Hotel Transylvania, Mavis (Selena Gomez), using her remarkable super hearing, overhears Dracula's (Brian Hull) intention to retire and pass the hotel to her. Excitedly, she informs her husband, Jonathan "Johnny" Loughran (Andy Samberg), who immediately shares his vision of renovating the hotel with Dracula. However, fearing that Johnny’s well-meaning ideas could lead to chaos and mishaps that might endanger the hotel’s guests and staff, Dracula deceives him by claiming there’s a real-estate law that permits only monsters to own the hotel, much to Johnny's dismay.
Among the hotel team, there's Blobby (Genndy Tartakovsky), a quirky green blob monster, along with Frankenstein (Brad Abrell), Wayne (Steve Buscemi), Griffin (David Spade), Murray (Keegan-Michael Key), as well as Wanda (Molly Shannon) — Wayne's werewolf wife, and Eunice (Fran Drescher), who is married to Frankenstein.
Professor Abraham Van Helsing (Jim Gaffigan), a former monster hunter and the great-grandfather of Ericka (Kathryn Hahn), devises a plan to assist Johnny. He introduces the Monsterfication Ray, a peculiar invention capable of transforming people into monsters and vice versa. After testing it on his pet guinea pig, Gigi, Van Helsing uses it on Johnny, who morphs into a dragon-like creature. In the process of trying to revert Johnny to his human form, Dracula accidentally turns himself into a human and shatters the ray's crystal. Van Helsing informs the duo that they can restore themselves if they retrieve a new crystal hidden in a cave in South America, prompting Dracula and Johnny to embark on their journey.
Dracula is hesitant to disclose these events to Mavis or Ericka, keeping Johnny at a distance. During their travels, a role reversal occurs: Johnny relishes his adventures as a monster, while Dracula, now mortal, becomes fearful of the human world.
To complicate matters, Dracula's friends — Frank, Wayne, Griffin, and Murray — unintentionally become human after drinking from a fountain affected by Van Helsing's ray. Mavis and Ericka, upon discovering Dracula and Johnny’s current predicament through the news, confront Van Helsing, who warns them of the dangerous mutations resulting from the ray’s exposure, urging them to find Dracula and Johnny before it’s too late.
As the group traverses the South American jungle, Johnny enjoys the ease of hiking as a monster, while Dracula struggles with newfound vulnerabilities. Their relationship begins to strengthen as Dracula teaches Johnny how to fly, moving toward an important confession about the fabricated real-estate law. However, just as this happens, the group locates them, and an upset Johnny, feeling excluded from Dracula's family, becomes increasingly volatile.
Determined to locate Johnny, Mavis sets off while Dracula and the others seek the crystal. Eventually, Mavis discovers Johnny in the cave, where they find the crystal, but his transformation into a monstrous state makes him unresponsive to attempts at reversing the effects. In a moment of deep remorse, Dracula willingly allows himself to be captured by Johnny, expressing heartfelt regret for his earlier deception and recognizing Johnny as family, which ultimately restores Johnny’s humanity.
With the gang back to normal, they return to a devastated hotel, wrecked by Gigi. After they transform Gigi back to her original state, Dracula laments the destruction but ultimately decides to let Mavis and Johnny rebuild the hotel according to their vision.
A year later, Mavis and Johnny proudly unveil the newly reconstructed Hotel Transylvania to Dracula, who finds joy in their creative efforts.
