The film opens centuries ago in Transylvania. Dracula (Adam Sandler), Frankenstein (Kevin James), Wayne (Steve Buscemi), Murray (Keegan-Michael Key), and Griffin (David Spade) are on a train in disguise. They are found by monster hunter Abraham Van Helsing (Jim Gaffigan) when he lights a match that scares Frank out of his disguise. The monsters run to the roof of the train where Drac pushes his buddies off for safety (even though they fall hard against trees) so that he can take on Van Helsing himself. Drac shapeshifts into a mouse to trick Van Helsing so he gets knocked off by the tunnel bridge. For years, Van Helsing continues to go after Drac, only to be foiled over and over again, until he seemingly gives up.
In the present day, Drac has a wedding organized at Hotel Transylvania between two prickly monsters. The bride is having pre-wedding jitters, but Mavis (Selena Gomez) manages to calm her down and convince her that the groom is her zing, and that it only happens once. The wedding goes on, and Blobby (Genndy Tartakovsky) officiates the ceremony, which is then ruined when Tinkles, the giant puppy adopted by Dennis (Asher Blinkoff), comes running in, knocking things over and spreading drool everywhere.
During the reception, Drac meets a beautiful Frankenstein-esque monster, Frankenginger (Allison Hammond), who is the cousin of Frank's right arm (meaning they have the same gigantic bicep). She dances with Drac, but he uses his powers to make Jonny (Andy Samberg), who is the DJ, play music that switches up the mood so Drac can get away. His friends are concerned since he hasn't been with anybody since his wife Martha died.
Drac is in his room going on the monster equivalent of Tinder, finding no luck because he is picky. Mavis overhears and believes he is just overworked and in need of a break. She sees a commercial on TV advertising a vacation for monsters, and she gets an idea.
The monsters board a plane flown by maniacal gremlins. Nearly every hotel regular and their family joins, like Wanda (Molly Shannon), Eunice (Fran Drescher), Vlad (Mel Brooks), and Griffin's new girlfriend Crystal (Chrissy Tiegen). The plane lands in the ocean, and they make it to the Bermuda Triangle where they board the cruise ship. Drac isn't thrilled because he thinks it's basically a hotel on the water. That's when he lays eyes on the ship's captain, Ericka (Kathryn Hahn), and Drac experiences his first zing in over a century. Erick introduces herself to the monsters and then Drac, and he is unable to form a proper sentence since he is so lovestruck. Meanwhile, Dennis and Winnie (Sadie Sandler) have brought Tinkles with them in disguise.
Ericka goes to her private quarters, and we learn that she is really the great-granddaughter of Van Helsing, who is still alive, albeit with only his head, arms, and a machine in place of the rest of his body. They plan to fulfill their family's mission to kill Dracula by going to Atlantis and finding an ancient artifact that will ultimately end not only Drac, but every monster on that ship.
The monsters partake in activities, but Drac is too nervous to talk to Ericka, despite his friends' encouragement. Wayne and Wanda leave their litter of pups in a kids club so that they can finally get a break from them. Blobby gets seasick but ends up puking himself a son.
Ericka brings the monsters to a spot where they can go scuba-diving. As they swim, she gets into her personal submarine to go after Drac and fire wooden stakes at him. However, she finds herself touched when she sees him playing with Mavis, Dennis, and Jonny. Ericka ejects herself from the submarine before she is noticed, but Mavis takes a picture of Drac next to the sub and sees Erick swimming away in the picture, making Mavis suspicious. As Ericka swims to the surface, Frank, Murray, and Griffin overhear her grumbling to herself about how she wants to get Drac, but he's "teasing" her. This leads the guys to think she likes Drac too.
The guys tell Drac what they heard, and they try to convince him to ask her out on a date. Ericka approaches Drac, and he asks her something ridiculous, but she accepts his "invitation" to meet him that night while the ship is docked so the monsters can hang out on a deserted island. The two meet later where she tries to poison Drac with guacamole drenched in garlic oil, but it only makes Drac gassy. After the awkward moment passes, Drac mentions not being on a date since Martha died, and how he's had to raise Mavis on his own. Ericka finds herself relating since she never knew her parents and was only raised by her great-grandfather. Mavis then heads to the ship after Jonny tells her that Drac has a crush on Ericka. She interrupts the date, forcing Ericka to retreat. Mavis then tries the guacamole and lets out a little toot herself.
Ericka heads back to her room where Van Helsing pops his head out to continue discussing their plan. Wayne and Wanda happen upon them, and Van Helsing tranquilizes them so that they don't tell Drac about their plans.
The ship then heads toward Atlantis, which is basically a big monster casino with the Kraken (Joe Jonas) acting as a lounge singer. Frank can't help but gamble, despite Eunice telling him not to. While the monsters are playing, Ericka goes into the ruins of Atlantis to find the artifact, while Drac follows her, and Mavis follows him. Ericka finds the place holding the artifact, but she triggers a booby trap that launches an axe at her, which Drac catches before it hits her. With Drac's help, Ericka avoids the other traps, making it look like the two are dancing romantically. They reach the top and grab the artifact, causing the whole place to collapse. They swim out, and Ericka pulls an axe stuck in Drac's head, but Mavis sees this and thinks Ericka is trying to hurt him. Mavis uses her powers to pull Ericka off Drac, but he tries to explain that he zinged. However, Ericka tells him that they cannot be together because she's human and he's a monster. She takes the artifact and goes, leaving Drac totally heartbroken.
With the artifact in their possession, Van Helsing decides to host a dance party for the monsters. They are all gathered in one big location, and he reveals himself to the monsters, though Drac doesn't recognize him at first. Van Helsing opens the artifact, revealing a sheet of music. He plays it on a keyboard, making a dubstep kind of beat that awakens the Kraken and makes him terrifying, causing him to attack the monsters. They try to escape, but he destroys the bridge. The Kraken grabs Drac and starts to squeeze him into unconsciousness. Mavis tries to save him, but she gets caught too. Ericka realizes how wrong she was, and she rides Tinkles to go and save Drac. She kicks the Kraken in the eye, making him drop Drac. She catches him and admits to Van Helsing that she zinged for Drac, causing Drac to wake up in delight. In the chaos, Ericka helps Mavis save the wolf pups, changing Mavis's mind about her.
The Kraken continues to attack, so Jonny takes out his turntables to play music with good vibes to soothe the beast. He starts with "Good Vibrations" by The Beach Boys. This works for a bit, but Van Helsing plays the bad beats louder, and the Kraken goes back to being possessed. Jonny tries "Don't Worry, Be Happy", which briefly works too, but Van Helsing's music is too powerful. The Kraken grabs Drac and Jonny and almost eats them, until Jonny unleashes his secret weapon...the Macarena. This gets all the monsters to dance, and is powerful enough to keep the Kraken happy. Even Van Helsing cannot resist dancing, but this causes him to fall over the edge. Drac flies down and saves him, causing Van Helsing to realize he was wrong about the monsters. He apologizes to them and offers them all full refunds.
The monsters return to the hotel. Wayne and Wanda are safe, but they enjoyed being tranquilized so they plan to go back on the cruise for the holidays. Drac then takes Ericka to the roof of the hotel where he decides to propose to her. She babbles awkwardly like Drac did at first until all the monsters show up to witness this. Ericka finally says yes, and everyone cheers.
*CUT TO THE CHASE*
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Count Dracula has grown lonely in the century since his wife Martha died. Mavis thinks he is overworked and in need of a break, so she arranges for Drac, his family and all his monster buddies to go on a monster cruise. Drac finds himself in love with the ship's captain, Ericka, unaware that she is the great-granddaughter of legendary monster hunter Abraham Van Helsing. The two are planning to kill Drac once and for all after they reach Atlantis and find an ancient artifact that will destroy him.
Despite wanting to kill him at first, Ericka finds herself charmed by Drac, although Mavis grows suspicious. Once they reach Atlantis, they find the artifact, but when Ericka learns that Drac likes her, she tells him they can't be together because she is human and he's a monster, which leaves him devastated.
Van Helsing gathers the monsters for a dance party and uses the artifact (a sheet of music) to awaken the Kraken so that he can kill all the monsters. Ericka has a change of heart when she realizes she loves Drac too, so she helps save him, plus Mavis and the wolf pups. Jonny steps in to use his DJ turntables to make the Kraken feel positive vibes by playing the Macarena. Van Helsing dances too but ends up falling over a ledge, leading Drac to save him. Van Helsing realizes he was wrong about monsters and he makes peace with them.
Upon returning to the hotel, Drac proposes to Ericka, and she says yes.
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