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.
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. Will Shaggy and Scooby succeed?
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.
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.
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.
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.
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.