After learning Dr. Phibes consumed a large quantity of the new nano-tech formula, Shaggy and Scooby must quickly devise a plan to rid of every nano-bot inside his body before Phibes becomes completely unstoppable.

Now fully nano-powered, Dr. Phibes plans to blow up his new remote volcanic lair which would cause nuclear winter and mass extinction around the world. Meanwhile, Shaggy arms himself with Uncle Albert's super suit as he and Scooby must infiltrate the lair to once again put a stop to Phibes' evil plans.

Dr. Phibes' latest world domination plan includes producing a massive army of nano clones. Each clone represents a different part of Phibes' personality. Shaggy and Scooby must face their toughest task yet, but little do they know that if Scooby consumes too much of the nano formula, the more likely he will become immune to its effects. Meanwhile, Robi's spring cleaning creates even more chaos for everyone.

On the verge of a mental breakdown, Dr. Phibes decides to take a vacation while Shaggy and Scooby win tickets for a Mexican cruise -- the exact same cruise that Phibes is on.

After being evicted from the lair by his evil clone, Dr. Phibes moves in with Shaggy and Scooby. However, due to Phibes' incessant crank calls, the clone decides to do something that even the real Phibes would never consider -- activate their Doomsday machine.

Dr. Phibes and his agents and techies make a DVD of a horror movie with real monsters, and thanks to Robi's new 4-D entertainment system, the monsters invade Shaggy and Scooby's home. A pig named Bacon from a trailer Agent 2 was obsessing about also lounges around, and Scooby and Shaggy work on a way to stop the monsters and Phibes before he can make copies of the DVD.

After hearing Shaggy and Scooby comment on how he isn't good at butlering or much else, Robi thinks he's failed at his job and leaves. He leaves Sparky to take his place transmitting Uncle Albert's messages. Soon Agents 1 and 2 find him at his new job in a criminal hangout. Now, unless Shaggy and Scooby stop him, Dr. Phibes will be able to gain access to Uncle Albert's inventions, as well as discover where he's hiding. And to make matters worse, Robi won't survive the downloading process.

Dr. Phibes, tired of being outsmarted by our heroes, revises his nano formula to increase his IQ. It also inflates his head. Now, Shaggy and Scooby must stop him from releasing a gas that will drastically lower the world's intelligence.

Dr. Phibes plans to avenge his unhappy childhood by unleashing a stampede of genetically engineered chicken bulls on the Western Tri-State Fair. Shaggy and Scooby must now find a way to stop him, while facing purring vultures, a hissing goat, and an 11-foot cross-eyed rooster.

Both Zoinks and Groovy Don, the original dog and owner of Shaggy and Scooby, respectively, mysteriously return to cause some mayhem, courtesy of Dr. Phibes.

Dr. Phibes has discovered that Uncle Albert is actually in deep cover as a member of his evil staff—and Phibes is determined to find and annihilate him.