Both the handheld and console versions of the game have the story of Mystery, Inc. investigating a standard case at Hambridge University before discovering that a mysterious organization is using an enchanted book called the Tome of Doom to unleash real ghosts and other supernatural creatures upon the world. It is up to the gang to use the Tome of Doom to recapture all the monsters and ghosts and solve the mystery of who's doing this.
- Asteroids Monster: In the Game Boy Advance version, the boss fight against the Fire Ghost has him split into smaller ghosts when the Tome of Doom is used on him. After he's been split into the smallest ghosts fought in the game, those can then be captured in the Tome of Doom.
- Big Bad: Travis Sherman, head of ShermanTech who is using the Tome of Doom to acquire more land and an alpha wave modulator to brainwash people into buying his products, is a figurehead for Selena Drake, his employee who uses the Tome of Doom to assist in her plan to mind-control the world.
- Corrupt Corporate Executive: Travis Sherman, the head of ShermanTech. Aside from using the Tome of Doom to assist in land acquisition by scaring people away with the monsters to force the owners to sell, he also intends to use Selena Drake's alpha wave modulator to brainwash everyone into buying only the products his company makes.
- Final Boss: The last boss fought in both versions is the Fire Ghost summoned by Selena Drake.
- Identical Twin ID Tag: The second level features the Milton Brothers, a pair of twins who work as movie directors. To tell them apart, Earl Milton has a goatee and wears an orange jacket as well as a yellow-green beret and scarf, while Doug has a moustache and wears a dark green jacket as well as a blue beret and scarf.
- Kill It with Water: The Fire Ghosts are immune to the Tome of Doom until their flames are put out by luring them near sprinklers. The final boss fight against the giant Fire Ghost in the console version even has activating the sprinklers surrounding the Fire Ghost the key to defeating him in the first phase of the battle.
- Laugh Track: Both the console version and the handheld version of the game have canned laughter accompany the jokes made in the cutscenes.
- Mad Scientist: Selena Drake's goal is to use an alpha wave modulator to control everyone's minds.
- The Man in Front of the Man: Dr. Selena Drake initially appears to just be Travis Sherman's minion, but she usurps her boss after Scooby and Shaggy free Fred, Velma, and Daphne of their mind control.
- Mook Maker: The portals in the Game Boy Advance version, which keep spitting out enemies unless the Tome of Doom is used to neutralize them.
- Mythology Gag: The Tome of Doom looks similar to Sarah Ravencroft's spellbook from Scooby-Doo! and the Witch's Ghost. Its function as a tool for capturing ghosts also brings to mind the Chest of Demons from The 13 Ghosts of Scooby-Doo.
- Never Smile at a Crocodile: Alligators are commonplace hazards in "Bad Juju in the Bayou".
- "Scooby-Doo" Hoax: The first three levels end with unmasking a criminal disguised as a monster. The first level has Walter Peabody disguised as a ghost, the second level has Robert Zabrinski disguised as the Red Knight, and the third level has Mindi Stiles disguised as a Native American woman (a Southern belle in the Game Boy Advance version).
- The Unfought: In both the console versions and the Game Boy Advance version, Mindi Stiles and Dr. Selena Drake are the only criminals the player doesn't directly face in a boss fight, the bosses of their respective levels instead being the Giant Dust Devil and the Fire Ghost that Drake summons in a last-ditch effort to defeat Mystery, Inc.
- Wolfpack Boss: The boss fight of the penultimate level has Shaggy and Scooby using the Tome of Doom to capture a bunch of zombie enemies.