After receiving an urgent holographic transmission from Uncle Albert, Shaggy and Scooby travel to Switzerland, using their new and improved mystery machine, in order to thwart Dr. Phibes' efforts in interrupting an anti-global warming conference. Once Phibes realizes he's being followed, he counteracts by sending one of his most dangerous agents after them.

Shaggy's uncle disappears and leaves Shaggy with millions of dollars, so Shaggy and Scooby-Doo go to the mansion he left for them and start exploring. They see some of his inventions and then Shaggy sees a note about how his new invention is trying to be stolen by someone and now he must go into hiding. Now Scooby and Shaggy have to go and solve another mystery.

Dr. Phibes plans on unleashing an evil computer virus into the nation's weapon defense systems, but Uncle Albert gets word of it first. While intercepting the virus, Shaggy and Scooby unknowingly release the virus into their in-house's computer system, which soon takes control of every appliance and utility in the mansion.

Dr. Phibes' latest evil plot is to abduct three of the world's leading scientists in order to gain technologically advanced weapons. Shaggy and Scooby must prevent this by sneaking into the country club where the scientists are being honored and protect them at all costs. However, they also have to deal with Phibes' agents.

Dr. Phibes sets out to destroy the rainforest in search for the secret to eternal youth. Meanwhile, poachers try to stop Shaggy and Scooby.

Shaggy and Scooby decide to throw a housewarming party, but their neighbor and president of the Housing Association, Thurston Havansimp, sets out on derailing their plans. He threatens to cite them with enough code and permit violations to evict them from their house and the neighborhood. Meanwhile, Dr. Phibes finds about the party and sends a deadly robot to the Shaggleford Mansion with orders to annihilate the dynamic duo.

Shaggy and Scooby meet up with Fred, Velma, and Daphne at a military base where Dr. Phibes' agents use their new invisible technology to steal weapons.

Shaggy and Scooby are nominated for the "Mystery Solvers of the Millennium" award. However, at the ceremony, the mystery solvers begin disappearing one by one while Shaggy and Scooby must work fast to discover who's taking them before they're next.

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.

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.

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 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.

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.

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.

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.

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.