A short time after the first film, Mavis (Selena Gomez) and her fiance Johnny (Andy Samberg) are married, with the approval of her father Dracula (Adam Sandler) and the world has become aware of (and unfased by) the existence of monsters. Mavis later reveals to Drac that she is pregnant and a year later, she gives birth to a son named Dennis (Asher Blinkoff), who befriends Wayne's werewolf pup daughter Winnie (Sadie Sandler). Nearing his fifth birthday, Dennis has yet to grow his fangs and Drac worries that his grandson might not gain vampire powers. Noticing the dangers of Transylvania, Mavis starts to consider raising Dennis where Johnny grew up, much to Drac's disapproval.
In the aftermath of the death of Dracula's wife Martha (Jackie Sandler) at the hands of an angry mob, Count Dracula (Adam Sandler) designs and builds a massive five-star hotel in Transylvania in which to raise his daughter Mavis (Selena Gomez) and to serve as a getaway for all the world's monsters.
Misfit parapsychologists Peter Venkman, Raymond Stantz, and Egon Spengler are called to the New York Public Library after a series of apparent paranormal activities, where they encounter the ghost of a dead librarian but are frightened away when she transforms into a horrifying monster.
A vindictive woman, Carrigan Crittenden, is upset upon the reading of her late father's will that she was given creepy Whipstaff Manor in Friendship, Maine instead of his fortune, but she changes her tune when she learns that there is a hidden treasure within the property. She and her assistant Dibs go to the house attempting to investigate, but discover that it is haunted by a friendly ghost named Casper and his obnoxious prankster uncles, the Ghostly Trio (Fatso, Stretch and Stinkie), who immediately frighten them off the property. Carrigan tries multiple methods to rid the house of ghosts, but fails time and time again. Meanwhile, Casper sees a report of a paranormal therapist, James Harvey, and is immediately smitten with his teenaged daughter Kat. He quickly inhabits the television in Carrigan's hotel room in order to convince her to have the Harveys come to the manor to investigate the haunting.
An 18-year-old girl named Drew Decker (Carmen Electra) receives a threatening phone call while home alone one night. Drew is chased outside by Ghostface, who stabs her in the breast, removing one of her silicone breast implants. She is hit by a vehicle driven by her father (Mark McConchie), who was distracted by fellatio from his wife (Karen Kruper), and is then subsequently murdered by Ghostface.
In a warehouse, the Mystery, Inc. gang illustrates a plan to catch the Luna Ghost who has kidnapped Daphne Blake (Sarah Michelle Gellar), flying around with her bound and gagged which goes astray but ends with Shaggy Rogers (Matthew Lillard) and Scooby-Doo (voiced by Neil Fanning) causing the Ghost to be caught. The gang unmasks the Luna Ghost, who is revealed the janitor of the Wow-O-Toy Factory, Old Man Smithers, who wanted revenge after Pamela Anderson refused to go out with him (it is implied that he kidnapped Daphne, mistaking her for Pamela). After solving the mystery, constant arguments among the members of Mystery Incorporated about Fred Jones (Freddie Prinze, Jr.) taking credit for Velma Dinkley's (Linda Cardellini) ideas and Daphne always getting kidnapped cause the gang to go their separate ways, much to the dismay of Shaggy and Scooby.
In 1869, two brothers bury a mysterious chest from which the sound of drumbeats can be heard. A century later, 12-year-old Alan Parrish escapes from a group of bullies to a shoe factory owned by his father, Samuel Parrish. When Alan accidentally damages a machine, Carl Bentley, an employee at the factory and Alan's friend, is blamed and dismissed. The bullies attack Alan and steal his bicycle. Alan follows the sound of tribal drumbeats to a construction site, where he finds a chest containing a board game called Jumanji, and takes the game home.
Abandoned by their father deep in a forest, young Hansel and Gretel enter a gingerbread house and are captured by a cannibalistic witch. The witch forces Hansel to continuously eat candy to fatten him up, and enslaves Gretel, ordering her to prepare the oven, but the siblings outsmart her and incinerate her in the fire of the oven. In the fifteen years that follow, Hansel and Gretel become famed witch hunters, slaying hundreds of witches. The pair find that they are somehow immune to spells and curses, but the incident in the gingerbread house has left Hansel diabetic. He needs a shot of insulin every few hours or he will get sick and die.
Katie (Jenny McCarthy) and Becky (Pamela Anderson) are talking about a tape, which Katie thinks is a sex tape, but Becky refers to a cursed tape (The Ring). After several odd occurrences, they die. In a farm outside Washington, D.C., widowed farmer and former reverend Tom Logan (Charlie Sheen) and his clumsy younger brother George (Simon Rex) discover a crop circle, saying "Attack Here!" (Signs).
Five years after saving New York City from the demi-god Gozer, the Ghostbusters—Egon Spengler, Ray Stantz, Peter Venkman, and Winston Zeddemore—have gone their separate ways after having been sued by the city for property damage and barred from investigating the supernatural, forcing them out of business. Ray owns an occult bookstore and works as an unpopular children's entertainer with Winston, Egon works in a laboratory on the Columbia University campus, conducting experiments into human emotion, and Peter hosts a pseudo-psychic television show. Peter's former girlfriend Dana Barrett has had a son, Oscar, with a violinist that she married then divorced when he received an offer to join the London Symphony Orchestra. In order to take care of her baby, Dana quit her former cellist profession and now works as a restorer at the fictional Manhattan Museum of Art, working to prepare a malevolent-looking portrait of a legendary sixteenth-century tyrant named Vigo the Carpathian of Moldavia for an upcoming exhibition.
Mystery Inc. (Fred, Daphne, Velma, Shaggy and Scooby-Doo) attend the opening of an exhibition at the Coolsonian Criminology Museum commemorating their past solved cases with monster costumes on display. However, the celebrations are interrupted by the Evil Masked Figure who steals two costumes using the reanimated Pterodactyl Ghost. The gang are ridiculed by journalist Heather Jasper Howe who starts a smear campaign against them. Concluding an old enemy is the mastermind, the gang revisit old cases, dismissing the former Pterodactyl Ghost, Jonathan Jacobo, due to his death during a failed prison escape, they guess Jeremiah Wickles, the Black Knight Ghost’s portrayer, is the culprit.
Shaquille O'Neal and Dr. Phil awaken to find themselves chained to pipes in a spoof of Saw. Their host, Billy the Puppet, reveals the room is filling with nerve gas. The only way to get the saws was to make a basket. Shaq misses twice, injuring Phil, but still managed to get the saws. Phil realizes they have to cut through their own feet. Shaq tricks Phil into doing so, but accidentally saws off the wrong foot, inadvertently leaving both men to die.
High school student Casey Becker receives a flirtatious phone call from an unknown person, asking her, "What's your favorite scary movie?" The situation quickly escalates as the caller turns sadistic and threatens her life. He reveals that her boyfriend Steve Orth is being held hostage. After Casey fails to answer a question correctly about horror films, Steve is murdered. When Casey refuses to cooperate with the caller, she is attacked and murdered by a masked killer. Her parents come home to find her body hanging from a tree.
While attending a preview of the film Stab, a film within a film based on the Woodsboro murders depicted in Scream, two Ohio Windsor College seniors, Maureen Evans and Phil Stevens are murdered by Ghostface. Phil is stabbed through the ear in a bathroom stall while trying to eavesdrop on strange whimpering noises. The killer, wearing a Ghostface costume, then returns to the screening and sits beside Maureen, before mortally stabbing her. At first the audience believe she is part of the raucuous acting out by audience members, until she falls dead in front of the cinema screen.