When Furrball inadvertently causes a continental crack-up, Dennis Coyote, Justin Puppy, Bubsy Bobcat, R1/Kid Rayman, Max Goof, PJ Pete, Little Beeper, Flap Platypus, and Zippy Doggenbottom get separated from Aleu, Kate, Humphrey, Pistol Pete, Gwen Doggenbottom, Odie the Puppy, Gromit, Iggy and Lemmy Koopa, and go on a high-seas quest aboard a floating iceberg. Along the way, they reunite with The Fox(from Grimm's Fairy Tale Classics) and make some new friends, but a group of villainous misfit pirates(led by Wolf from the Grimm's Fairy Tale Classics episode "The Wolf and the Fox) are determined to capsize their journey home. Wolf's first mate, a female bobcat named Sheila, joins the herd after she is left for dead. Meanwhile, Furrball, in a subplot, finds a map that leads him to a secret island full of yarn.
On the journey back home, Dennis and the herd will recruit with: The Fox(from Grimm's Fairy Tale Classics), Oggy the Cat(from Oggy and the Cockroaches), Jerry the Mouse(from Tom and Jerry), La Brea & Marshall(from Dino Babies), Roofus the Roller Roo & Kooky A. Bird(RSA/Roller Kingdom), Courage the Cowardly Dog, and Red Rover(Mattel version) While waiting for Dennis and the herd to return home, Aleu, Kate, Pistol Pete, Gwen Doggenbottom, Odie the Puppy, Gromit, Iggy and Lemmy Koopa will befriend Olivia(from Oggy and the Cockroaches) and Scooby Jr.
- Jaleel White as Dennis Coyote
- Jason Marsden as Justin Puppy
- Tom Kenny as Bubsy Bobcat and Zippy Doggenbottom
- Lacey Chabert as Aleu
- Hayden Panettiere as Kate
- Mike Vaughn as Iggy Koopa
- Lani Minella as Lemmy Koopa
- Gage Munroe as Max Goof
- Rob Paulsen as PJ Pete
- Caitlin Hale as Pistol
- Stuart Ralston as R1/Kid Rayman
- Gregg Berger as Odie
- Frank Welker as Furrball, Little Beeper and Seymour
- Linda Cardellini as Gwen Doggenbottom
- Justin Long as Humphrey
- Jim Cummings as the GFTC Wolf
- Keith Scott as Flap Platypus & Danny Dingo
- Eddie Korbich as Red Rover, Ootsie & Bootsie Snootie
- Eddie Garvar as the Blue Aardvark
- Don Messick as Azrael
- Marty Grabstein as Courage the Cowardly Dog
- Paul Schoeffler as Katz
- James Patrick Stuart as Joey
- Don Michael Paul as Oggy
- Townsend Coleman as Roofus
- Dave Cohen as Kooky A. Bird
- John de Lancie as Discord
- Grey DeLise as Sheila Bobcat
- Tara Strong as Olivia & Scooby Jr.
- Josh Peck as Theo Wolf
- Rude Dog and Springtrap(from the third movie fanmake) will both make a cameo in the film, when Furrball falls through Earth and passes them.
- This is the first time that Eddie Korbich will voice Red Rover.
- Shifty Dingo, Tom, Jerry and Gromit(not mentioned above) are the only characters in this film with non-speaking roles.
- Theo Wolf(from The Wolf and the Fox 2) will appear in this film(with a minor role), but he appears as a teenager, unlike in The Wolf and the Fox 2, where he was a kid.