Dracula (voiced by Adam Sandler) is the owner and creator of Hotel Transylvania, a five-star resort where the world's monsters can be safe from human civilization. Dracula invites some of the most famous monsters like Frankenstein (Kevin James) and his wife Eunice (Fran Drescher), Murray the Mummy (Cee Lo Green), Wayne and Wanda Werewolf (Steve Buscemi and Molly Shannon), Griffin the Invisible Man (David Spade), Bigfoot, Steve the Blob, and other monsters to celebrate the 118th birthday of his daughter Mavis (voiced by Selena Gomez). However, Mavis prefers to explore the outside world with her father's permission, but the village he directs her to is actually an elaborate deception to convince her of the threat of humans enough to coax her back.
However, this charade inadvertently attracts the attention of an ordinary young traveler named Jonathan (voiced by Andy Samberg) who was exploring the surrounding forest and followed the staff to the hotel. Once Jonathan enters the hotel, Dracula frantically attempts to hide him from the patrons such as disguising him as a Flesh Golem named Johnny-stein with the later hasty cover story of being a relative of one of Frank's body parts. Eventually, Jonathan is discovered by Mavis and company, forcing Dracula to claim he is going to arrange Mavis' birthday party with a young perspective. In doing so, Jonathan manages to charm everyone at the hotel, especially Mavis. Eventually, even Dracula begins to like the human taking him into his confidence about his family's traumatic past after the vampire notices the young man knows something about them in a respectful manner.
Unfortunately, Chef Quasimodo Wilson (Jon Lovitz) realizes Jonathan is human and captures him to cook him, forcing Dracula to directly intervene by magically freezing the chef. Eventually, the birthday party happens and it is a raucous success until Dracula freaks out when Mavis and Jonathan have an innocent kiss. A ranting Dracula accidentally lets it slip that he tricked Mavis at the fake village and Mavis is outraged at being manipulated by her own father. Things get worse when a still-frozen Chef Quasimodo interrupts the party as the Fly (Chris Parnell) translates his frozen language to the clientele which states that Jonathan is actually a human. Even as the clientele are revolted, Mavis still accepts and expresses her desire to be with Jonathan even though he is human. For his part, Jonathan feels obliged to reject Mavis for her father's sake and leaves the hotel. Afterward, Dracula realizes that in his efforts to protect Mavis, he has broken her heart and now she tearfully wants to stay at the hotel forever.
Wishing to undo his mistake, Dracula persuades his friends to help him find Jonathan and even risks his destruction by venturing out in the daylight to do so. Learning that Jonathan is about to board a flight out of Transylvania Airport shortly, they race on and enter a town en route. At that town, Dracula and company are stunned to see the humans having a 'Monster Festival'. To clear a path, Frankenstein tries to scare them, but finds the humans are cheerfully welcoming them instead and even provide a shaded route through the town for Dracula to proceed at maximum speed.
However, Dracula finds that he is too late with Jonathan's plane taking off. With no alternative, Dracula desperately flies after it in broad daylight despite being hurt by the sun. With much effort, Dracula manages to reach the plane and resorts to mind-controlling one of the pilots (Brian Stack) to apologize and tell Jonathan that he wants him to return to be with his daughter. Jonathan accepts Dracula's apology and Dracula manipulates the plane back to the airport.
Later, Dracula returns Jonathan to Mavis, who tells her that she's his 'zing' and the reason why he had to reject her. Dracula gives his blessing to their relationship, Jonathan and Mavis kiss and the hotel has another party to celebrate his daughter's liberating coming of age before Jonathan and Mavis set off on their travels.
The film ends with Dracula and his friends being shown in traditional animation (in the style of Genndy Tartakovsky's cartoons) during the credits.