Four cartoon villains — Professor Calamitous, Vlad Plasmius, Mr. Crocker, and Plankton — have formed a coalition called the Syndicate. Their shared goal: drain energy from every animated world they can reach and channel it into a single Doomsday Machine. Jimmy Neutron's Goddard detects the anomaly first. Jimmy uses Goddard to open portals and recruit SpongeBob, Danny Phantom, and Timmy Turner. Together, the four heroes push through five worlds — traversing environments unique to each of their universes, gathering the components of Goddard that were scattered by the portals, and working toward the machine at the center of the Syndicate's plan.