In 1895, after his wife Martha was killed by an angry human mob, Count Dracula commissions and builds a massive monsters-only hotel in Transylvania, in which he raises his daughter, Mavis. The hotel also serves as a safe haven and a getaway for the world's monsters from fear of human persecution. Famous monsters such as Frankenstein and his wife Eunice, Wayne and Wanda Werewolf and their massive immediate family, Griffin the Invisible Man, and Murray the Mummy often come to stay at the hotel.

In the present-day (2012), on Mavis' 118th birthday, Dracula allows his daughter to leave the castle to explore the human world, but he sets up an elaborate plan using his zombie bellhops disguised as humans to make them seem intimidating, and frighten her home. The plan works, but the zombies inadvertently lead a 21-year-old[8] human Jonathan "Johnny" Loughran back to the hotel. Drac frantically disguises him as a Frankensteinesque monster and passes him off as Frank's cousin "Johnnystein". Jonathan soon encounters Mavis and the two "Zing". Unable to get Johnny out of the hotel without notice, Drac quickly improvises that Johnny is a party planner, brought in to bring a fresher approach to his own traditional and boring parties. Johnny quickly becomes a hit to the other monsters, but this worries Drac, who is both jealous of Johnny's popularity and afraid that his friends will never return to the hotel if they find out about the lie. Drac orders Johnny to leave, but he is brought back by Mavis, who is unaware of Johnny's real species and feud with her father. After being shown the beauty of a sunrise by Johnny, Mavis is inspired to give humans another chance.

Meanwhile, the hotel chef Quasimodo, with the help of his pet rat Esmeralda, learns that Johnny is a human and kidnaps him to cook him. Drac intervenes and magically freezes Quasimodo to keep him from telling anyone that Johnny is human. Drac leads Johnny to his quarters and shows him a painting of Martha, allowing Johnny to realize why Drac built the hotel and became overprotective of Mavis. Johnny then agrees to leave for good, but Drac, noticing that Mavis and Johnny's feelings for each other are real, persuades him to stay for the time being to avoid ruining Mavis's birthday. Drac and Johnny begin to bond and have fun together.

The party is a great success the next night, and Mavis looks forward to opening a gift from Martha. However, when Johnny and Mavis share their first kiss, Drac overreacts, and in his outburst, inadvertently confesses to deceiving Mavis with the town. A still-frozen Quasimodo bursts in and Mr. Fly reveals from his frozen speech that Johnny is a human disguised by Drac. The guests are shocked and outraged by the deceit at play, but Mavis is undeterred and wants to be with Johnny. Johnny feigns uninterest in Mavis and rejects her out of respect for her father and leaves the hotel.

A heartbroken Mavis flies onto the roof with her mother's gift, and Drac follows her in hopes of comforting her. He learns the present is a book about how Drac and Martha "Zinged" and fell in love. Drac realizes he no longer knows humankind's true tolerance of monsters. After apologizing to the patrons, Drac persuades Frank, Wayne, Griffin, and Murray to head out into the human world to help him find Johnny, and with the scent-tracking ability of Wayne's daughter, Winnie, they learn that he is about to catch a flight back to the United States.

The four head to the airport, but are held up in a town celebrating a Monster Festival along the way. Frankenstein attempts to scare away the assembled crowd of humans with a loud roar but instead receives wild applause and adoration. He then gets the humans to agree to help, and a team of men dressed as vampires provides Drac shelter from the sunlight while he rushes to the airport. Drac arrives to see Johnny's plane taking off, and he gives chase in bat form, burning in the sunlight. After getting Johnny's attention, Drac makes his way to the windshield of the plane and uses his mind-controlling power on the pilot to help him apologize, stating that Mavis has grown up and can make her own decisions. Johnny accepts his apology, and Drac manipulates the pilot to return to the Transylvanian airport.

Drac returns Johnny to Mavis, announcing that he approves of Johnny. Johnny confesses to Mavis that their "Zing" was mutual and the two kiss. The monsters finish celebrating Mavis' party, impressing the hotel guests.

Some time after the events of the first film, Mavis and Johnny are finally married, with the approval of her father Count Dracula. A year after the wedding, Mavis reveals to Drac that she is pregnant and later gives birth to a baby boy whom the couple name Dennis, nicknamed "Denisovich" by Dracula.

As Dennis's fifth birthday nears, he has yet to grow his fangs and Drac worries that his grandson might not gain vampire powers. Noticing the potential dangers her son might face living in Transylvania, Mavis starts to consider moving to Johnny's hometown in California in order to give Dennis a more "normal" childhood, much to Drac's disapproval. Drac tells Johnny (who does not want to leave the hotel either) to bring Mavis to California to visit his parents, Mike and Linda, but to make sure to keep her distracted so that she will not move, leaving Dracula to "babysit" Dennis.

Convinced that Dennis is a "late fanger", Drac enlists his friends Frank, Wayne, Griffin, Murray, and Blobby to help train Dennis to become a monster, but every attempt that they try fails. Drac and the gang then go to Camp Winnepacaca, Drac's childhood summer camp, only to sneak away after Drac finds out that the camp has become much safer and child-friendly. Drac attempts to hurl Dennis from a tall, unstable tower to pressure the boy's transformation into a bat, but he fails to transform and Drac flies down and rescues him at the last second.

Meanwhile, in California, Mavis enjoys exploring the more human world. When the couple arrive at Mike and Linda's house, Linda unsuccessfully attempts to make Mavis feel more comfortable by covering her room with spooky, Halloween decorations and inviting other monster/human couples over. Feeling like a stranger, Mavis retreats up to the roof, and Johnny tells her that if they stay together, Dennis will live normally, persuading her to stay at the hotel. However, Johnny then discovers a video of Dennis falling that was filmed by the campers, and he and a furious Mavis go back to Transylvania, with Drac and his friends reaching the hotel at the same time. Mavis confronts her father for putting Dennis in grave danger and failing to accept him as a human, and shows him a pop music remix parody of Dennis in danger and Drac arguing with the staff. Mavis says that they will move out of the hotel after Dennis's birthday party.

The night before the party, Drac hosts Johnny's family, and finds out that Mavis invited his father Vlad. As Vlad is more hateful of humans than he was, Drac tells Johnny to have his family disguise themselves as monsters. The next day, Vlad arrives with his monstrous bat-like servant Bela, and meets Dennis for the first time. Believing that fear will cause Dennis' fangs to sprout, Vlad possesses a stage performer, named Brandon, dressed as Dennis' favorite TV monster Kakie to scare him, but Drac shields his frightened grandson at the last moment, breaking Vlad's hold over the performer. Mavis mistakenly believes that Drac was responsible for the ruse, and while the family argues about whether or not Dennis can be happy in California, a guilt-ridden Dennis flees the hotel and enters the forest with Wayne and Wanda's daughter Winnie, who has a crush on him, in tow.

Irritated with Vlad, Johnny and his family expose themselves, and an irate Vlad reprimands Drac for accepting humans. Upon hearing that Dennis is a human, Bela attacks him and Winnie in their treehouse and abducts them. When Bela injures Winnie and threatens to destroy the hotel, Dennis's anger causes him to instantly grow his fangs and develop his vampire abilities, and he bashes up Bela. A furious but defeated Bela calls his giant-bat minions, but Drac, Johnny, Mavis, Dennis, and the rest of the monsters team up to defeat Bela's minions and drive them away, while Bela is shrunk by Vlad, who has been won over by Drac's claim that humans now coexist peacefully. With Dennis finally embracing his vampire abilities, Johnny and Mavis decide to continue raising him in Transylvania, and they resume the party with his friends and family.

Back in 1897, Dracula and his friends travel in disguise on a train to Budapest. However, Dracula's arch-nemesis Professor Abraham Van Helsing boards the train and unveils the monsters; the monsters escape by climbing through the roof, and Dracula pushes his friends off the train for their safety. Van Helsing becomes obsessed with destroying Dracula, but is constantly outsmarted by him.

In the present-day, a few weeks after the second film, Dracula is running his hotel business smoothly with Mavis and Johnny. Drac is depressed that he has remained single since his wife Martha's death despite his attempts to meet someone. Misinterpreting this as stress from overwork, Mavis books a cruise so they can all take a break and spend more time together as a family. Dracula, Johnny, Mavis, Dennis, Vlad, and the hotel guests board a cruise ship called Legacy. Dracula sees the ship's human captain, Ericka, and immediately falls in love with her at first sight, something that he thought was impossible as he had already "zinged" before.

Ericka afterwards goes to a private and secret room on the lower decks where she meets up with Abraham Van Helsing, secretly her great-grandfather. Van Helsing has almost entirely mechanized his body to avoid death, and has a plan to eliminate all the monsters: on the cruise's arrival at the lost city of Atlantis, he will use an Instrument of Destruction in Atlantis' ruins. Van Helsing makes Ericka promise to not assassinate Dracula beforehand, but she makes repeated unsuccessful attempts to do so anyway. Dracula's friends hear Ericka complain about her inability to get him and misinterpret this as a sign of affection. Dracula nervously asks Ericka out on a date, and she accepts since she sees this as another opportunity to kill him. As they dine on a deserted island, Ericka unexpectedly begins to fall in love with Drac, after they learn about each other's pasts about losing their loved ones - for Dracula, it was his beloved wife Martha and for Ericka, it was her parents.

Mavis discovers Dracula is interested in Ericka and becomes suspicious of Ericka's motives. The cruise ship reaches Atlantis, which has been converted into a casino; Dracula decides to tell Mavis the truth about Ericka but gets distracted seeing Ericka enter an underground crypt. Drac follows her, with Mavis not far behind, and learns that Ericka is after a "family heirloom". With Dracula's help, she evades the booby traps around the object and escapes. Mavis arrives and confronts them, and Dracula confesses that he "zinged" with Ericka, to Mavis' surprise and confusion. After Ericka is told what a "zing" is, her inner guilt about lying to Dracula forces her to reject Dracula's feelings for her, leaving Dracula heartbroken and Mavis feeling guilty.

A regretful Ericka gives Van Helsing the object - the Instrument of Destruction - and he sets a trap for the monsters at a dance party. Noticing that Dracula is still depressed about Ericka, Mavis takes advice from Johnny and tells her father to talk to Ericka, admitting that she was afraid of him leaving her, which allays Drac's fears. Van Helsing shows up and pushes away the DJ, and a saddened Ericka is forced to reveal that she is his great-granddaughter. Van Helsing unveils the Instrument of Destruction - a case for a music note sheet - and plays a song that drives a friendly Kraken living near the island to attack the monsters. Dracula tries to stop the evil Kraken, but gets injured. Ericka saves Dracula from the evil Kraken and pleads with her great-grandfather to stop the destruction, confessing her love for Drac. This infuriates Van Helsing, and he attacks them both.

To pacify the Kraken, Johnny opens up a portable DJ kit and plays positive songs ("Good Vibrations" and "Don't Worry, Be Happy") to beat Van Helsing's song. Upon playing the "Macarena," the Kraken is relaxed and happy for good; Van Helsing is unable to counter the song as the humans and monsters begins to dance, including the music sheet, which rips itself to pieces during the process. When Van Helsing also dances, he accidentally slips and falls, but Dracula saves him. Touched by the act of kindness, Van Helsing apologizes to the monsters and gives everybody a full refund for the cruise, before sending them back. Back at Hotel Transylvania, Dracula proposes to Ericka, who gets tongue-tied at the question before accepting.

During the celebration of the 125th anniversary of Hotel Transylvania, Mavis overhears Dracula's plans to retire and leave the hotel to her and Johnny. She tells Johnny who excitedly tells Dracula his plans to renovate the hotel. Worried about Johnny ruining the hotel, Dracula lies to him saying that there is a "monster real-estate law" which only lets monsters own the hotel, disappointing Johnny.

Van Helsing decides to help Johnny using a ray that turns humans into monsters and vice versa; after testing it on his guinea pig Gigi, he uses it on Johnny who turns into a dragon-like monster. Learning about monster Johnny, Dracula tries to turn him back to normal, but accidentally turns himself into a human and breaks the ray's crystal. Van Helsing tells Dracula and Johnny that they can still turn themselves back to normal by getting a new crystal which lies in the Cave of Reflexion in South America, so Dracula and Johnny set off to do so.

Dracula's friends Frank, Wayne, Griffin and Murray end up becoming humans as well, as a result of drinking from a fountain that was contaminated by the ray. Mavis and Ericka confront Van Helsing after learning about Dracula and Johnny's whereabouts in the news, but he warns them about the effects of the ray, as humans who become monsters continue to mutate and become more hostile as time goes on. With this in mind, the rest of the gang head to South America to find Dracula and Johnny.

While traveling through the South American jungle, Dracula and Johnny begin to bond, and Dracula eventually begins to confess that he lied about the monster real-estate law, but the rest of the group find them. Things turn sour when Dracula admits his deception regarding passing over the hotel to Mavis and Johnny. This prompts an upset Johnny to believe Dracula does not consider him family and to mutate further before running away.

Mavis goes to find Johnny while Dracula and the rest of the gang go to the Cave of Reflexion. Mavis finds Johnny, but the transformation has turned him very volatile. She leads him to the Cave of Reflexion where they finally find the crystal. When Mavis tries to turn Johnny back to normal, nothing happens due to him being too frenzied. In desperation, Dracula lets himself get captured by Johnny and goes on a remorseful tangent about how wrong he was about Johnny and how he now sees the best in him, finally acknowledging him as family. This brings Johnny back to his senses, and he is returned to human form.

With Dracula and his friends turned back to normal, they return home only to find the hotel has been destroyed by Gigi. After turning Gigi back to normal, Dracula bemoans his loss. He soon decides to let Mavis and Johnny rebuild the hotel to their liking.

One year later, Mavis and Johnny show Dracula the re-built Hotel Transylvania which he comes to enjoy.