Plot

After one experiment, Johnny turns into a monster and everyone else becomes human. Now it has to be seen whether they will be able to reverse this experiment.

When Van Helsing's mysterious invention, the "Monsterfication Ray", goes haywire, Drac and his monster pals are all transformed into humans, and Johnny becomes a monster. In their new mismatched bodies, Drac, stripped of his powers, and an exuberant Johnny, loving life as a monster, must team up and race across the globe to find a cure before it's too late, and before they drive each other crazy. With help from Mavis and the hilariously human Drac Pack, the heat is on to find a way to switch themselves back before their transformations become permanent.—Sony Pictures

After the eventful holiday in Hotel Transylvania 3: Summer Vacation (2018), Count Dracula has a little announcement to make. However, as ecstatic Johnny starts meddling with Van Helsing's mysterious contraptions, all hell breaks loose, and suddenly, a new tenant sets foot in the ancient monster resort. Now, the Prince of Darkness isn't feeling himself, and his son-in-law, too, is someone else. As friends and family do their best to avert the inevitable, a frenzied journey to the corner of the Earth begins. Can Mavis and her monstrous dream team right a wrong and stop the transformation that ruins everything?—Nick Riganas

During the celebration of the 125th anniversary of Hotel Transylvania, Mavis (Selena Gomez) overhears (due to her supersonic hearing) Dracula's (Brian Hull) plans to retire and leave the hotel to her. She tells her husband Jonathan "Johnny" Loughran (Andy Samberg) who excitedly tells Dracula his plans to renovate the hotel. Worried about Johnny ruining the hotel (Johnny has a good intention but has a tendency to cause accidents and leads to injuries to guests and workers of the hotel), Dracula lies to him saying that there is a real-estate law which only lets monsters own the hotel, disappointing Johnny.

Other staff of the hotel includes Blobby (Genndy Tartakovsky), a green blob monster. Party Monster (Richard Tyler "Ninja" Blevins). Frankenstein, Wayne, Griffin, Murray, Wanda (Molly Shannon), a werewolf and Wayne's wife, Eunice (Fran Drescher), Frankenstein's wife.

Professor Abraham Van Helsing (Jim Gaffigan) (former monster hunter and Ericka's great-grandfather who invented the "Monsterfication Ray") decides to help Johnny using a ray that turns people into monsters and the other way around as well; 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 a cave in South America, so Dracula and Johnny set off to do so. Dracula doesn't want to reveal the events to Mavis or Ericka and keeps Johnny away from them as well, before they embark upon their trip. In a role reversal Johnny enjoys travelling as a monster, and Dracula is now a mortal and is petrified at being in a human world.

Dracula's friends Frank (Brad Abrell) (Frankenstein, Eunice's husband), Wayne (Steve Buscemi) (a werewolf and Wanda's husband), Griffin (David Spade) (An invisible man) and Murray (Keegan-Michael Key) (An ancient Mummy) end up becoming humans as well, as a result of drinking from a fountain that was contaminated by the ray. Mavis and Dracula's wife, Ericka Van Helsing (Kathryn Hahn) 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 people who become monsters continue to mutate and become more hostile as time goes on (based on the observations of the effect of the ray on Gigi). 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 (Johnny likes hiking as it is really easy for him, but Dracula finds it very hard now that he doesn't have any of special powers like super strength or ability to fly. He has pollen allergies, is attacked by piranha in the river, is bitten by mosquitoes, none of which effects Johnny anymore), Dracula and Johnny begin to bond (Dracula teaches Johnny how to use his wings to fly), and Dracula eventually begins to confess that he lied about the monster real-estate law, but the rest of the group find them (Mavis uses her sonar powers to locate them in the jungle after Ericka gets the whole gang there on her blimp). 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 (and more and more enraged) before running away.

Mavis goes to find Johnny while Dracula and the rest of the gang go to find the crystal. Mavis finds Johnny, but the transformation has turned him very volatile. She leads him to the cave (by enraging Johnny by hitting him with rocks) 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 to their liking. A year later, Mavis and Johnny show Dracula the re-built Hotel Transylvania, which he comes to enjoy.