The gang visits a strange town on Halloween night to celebrate the holiday, but the festivities are soon interrupted when Shaggy and Scooby run into a witch's house while trick or treating. Much to the gang's surprise, Fred reveals that he ran into this same witch 11 years ago and has been afraid to solve a mystery on Halloween ever since. In the process of solving the mystery, the gang tries to convince Fred that it is possible to solve a mystery on Halloween night despite his superstitious belief.
The gang is in Britain for Velma's symposium speech on Christmas Eve, but the spirit of mystery is in the air when they meet a man who claims he will be haunted by three ghosts. While Scrooge's lack of articulateness and Fred's grudge against raccoons keeps the gang occupied, Velma discovers that the ghosts are not only there to show Scrooge the error of his ways. It seems the ghosts want to show her that her life would be far better without being oppressed by the gang's obsession with mysteries.
After being brutally beaten up by a monster, Shaggy and Scooby decide to quit the gang and hire replacements for themselves. Whilst providing on the job training for the newbies, Shaggy and Scooby realize replacing themselves isn't as easy as they had thought, particularly when a blood-sucking vampire appears.
When a giant creature called a Houndbeast attacks a dog show, Scooby goes undercover and enters the show to solve the mystery. However, internal struggles between the gang make it difficult to solve the mystery, including Velma and Shaggy switching personalities, Fred pretending to be a rich millionaire, and Scooby trying to earn the respect of the other dogs.
Shaggy inadvertently runs into his first crush, Amelia, who he discovers has decided to become a goth. Worried his personality isn't exciting enough for her, Shaggy decides to adopt the goth subculture. During Shaggy's "Goth Initiation," a plant monster attacks the goths' hangout. While the gang becomes focused on solving the mystery, Shaggy realizes that being a goth isn't a way to hide to his true self from others, but instead a way of expressing one's true self.
The gang meets British secret agent Jenny Vex, who attempts to enlist them in her mission of saving the world. It seems the supervillain Bubby has a dastardly plan to forever end the meal of breakfast, and has sent another secret agent, Minus, after Jenny and the gang. The gang has to trade their detective caps for spy gear in order to stop the supervillains from permanently eliminating breakfast from the menu!
When the gang returns to Velasco, where they had previously solved a mystery, they discover there is yet another mystery in the town. The five friends have to solve their most difficult mystery yet when an evil force possesses the Mystery Machine and tries to hunt the gang down. While the gang flees for their lives, Fred goes through intense denial about his beloved van.
Daphne takes the gang to an Ice Hotel, where a caveman frozen in ice was recently discovered. While Daphne is acting very peculiar, the Ice Man thaws out and goes on a rampage around the hotel. The gang has to solve yet another mystery, while contending yet again with Velma's extreme fear of water (in all its forms) and Daphne's very strange behavior.
The gang drives to Florida to see Shaggy's grandmother who is in a nursing home there. Worried that his grandma will be disappointed in him, Shaggy pretends he is leader of the gang and Daphne is his girlfriend. However, as always, the gang has to solve another mystery, though none of them are sure which is more upsetting: the Ape Man running around the nursing home or the horrific shorts Fred is wearing to keep him cool.
Fred brings the gang to the local garbage dump to find a rare part for the Mystery Machine, inadvertently resulting in Scooby running into his old kennel mate Axel. After Axel acts very coldly to Scooby, he and Shaggy become determined to solve the mystery of the Trash Monster, which Axel is also trying to capture. Meanwhile, Daphne tries to become exactly like Fred to find out how he feels as the leader of the gang.
Velma is offered 10 million dollars by the Brainsplosion company, who wants to use a video game code she made with her friend Zara for the sequel to their successful game Protein Titans. However, Velma is forced to make a very difficult decision when the company offers her a five-year contract. Meanwhile, the rest of the gang attempts to solve the mystery of the Ghost Chef, the villain from the Protein Titans game, who has suddenly become real.
The gang visits Salem, Massachusetts to go to a historical festival, but quickly after they arrive, the events of Salem Witch Trials begin repeating themselves. A legendary demon, supposedly conjured by a woman accused of being a witch, has returned to Salem to seek vengeance on the townspeople. Fed up with the prejudice witch stereotyping, Daphne speaks out against the mayor of the town, causing her to be accused of witchcraft herself.
Fred and the gang are requested to help solve the mystery of the escaped villain Professor Huh?, but they soon run into Fred's childhood friend, Rose, who acts very aggressively towards him and is trying to compete against the gang to solve the mystery first. To make matters worse, Professor Huh? is notorious for not leaving any clues and being as elusive and confusing as possible. The gang tries to solve their most difficult mystery yet, while learning something shocking about Fred in the process.
Fred's old friend Rose makes the gang prime suspects in the Professor Huh? escape, and they are forced to flee from the police. After narrowly escaping from a rocket and Professor Huh?, the gang attempts to go incognito in order to solve the mystery. A high-speed chase from the police quickly ensues, and the gang realizes that the Professor Huh? mystery goes much deeper than they could have ever imagined.
The gang goes to an arcade which Shaggy frequented in his childhood, so he can finally get Pizza Pup, a stuffed dog prize that he has been desiring since he was a kid. However, what they don't realize is that the arcade's deactivated robotic mascot, Pizza O'Possum, has come to life and wants to frighten everyone away from the arcade.
Fred takes the gang to a seafood restaurant. Their plans for a much-needed relaxing dinner abruptly end when they discover their waiter is none other than Captain Cutler, a previous villain who has eluded them. It seems though, that Captain Cutler has changed his ways, when he requests their help in capturing Half-Beard, a ghost who is scaring all the customers away from Cutler's restaurant.