One seemingly normal day, SpongeBob and Squidward are on their way to work when huge asteroids start raining down on Bikini Bottom. A huge drop of goo falls on Squidward, causing the top part of his face to turn orange and become a morphoid. He chases SpongeBob around the perimeter of someone's house until Patrick intervenes. Jimmy Neutron then arrives to take them to the Mawgu lair. The morphoids spawning from the asteroids start taking over Bikini Bottom.
SpongeBob and Patrick explore the vast Mawgu Lair, where they meet Danny Phantom and Tak again, and the new Evil Syndicate composed of Technus, Beautiful Gorgeous, Traloc, and Plankton. Zim and Dib then arrive, with Zim joining the good guys, and Dib joining the Syndicate. They make a plan to stop the morphoids when the Wise Old Crab arrives to inform them about the technology in the lair. Jimmy is able to figure it out, and fits everyone with weapons fitting their personality: Jimmy receives some sort of helmet and a tennis racket, SpongeBob gets a bubble blower, Danny receives a device that allowed him to partly clone himself, Tak is given a staff, and Zim receives a plunger (which refers to as "a plunger of doom"). Meanwhile, on the evil side, Technus receives an arm blaster, Plankton is given a hammer that allows him to grow (about to the height of Jimmy, Zim, and SpongeBob), Traloc receives a pouch of magic potions, Dib is given a gun-like balloon launcher, and Beautiful Gorgeous receives a heart-shaped megaphone.
They travel through Bikini Bottom, and they meet Bubble Bass, who grows gigantic and becomes a zombie after eating his last patty which had just been covered in goo. The group battles an army of Morphoids to free Gary, Squidward, and Patrick from the goo. They defeat Bubble Bass by feeding him Krabby Patties, causing him to vomits a large amount of goo onto SpongeBob. SpongeBob doesn't mutate like the others, but suddenly speaks in evil voice when back at the lair getting washed of the goo, saying "Your world will end! My Globs of Doom will rain over your world... and take control... Bwaa!! Haa!" The Wise Old Crab informs them that a huge robot called the Vessel of Portentia is hidden in the Mawgu Lair, and requires four special components to power it up.
The group moves to Zim's town, where GIR was playing with a taco that happened to be the first component of the Vessel Of Portentia. GIR becomes mutated by the goo before giving, picks up the component, and runs away. The protagonists free Ms. Bitters, Gaz, and Professor Membrane from the goo, before facing the corrupted GIR, who tires out of attacking the heroes and is then beat up out of being possessed. The house drops some goo, which lands on SpongeBob. SpongeBob celebrates getting the component, but interrupts himself in the evil voice that threatens it will be "smugglering" the planet. The group discovers that the absorption of goo in SpongeBob's body has created a wavelength enabling the leader of the Morphoids to talk through him. SpongeBob snaps out of it when he smells a Krabby Patty Patrick was holding.
Moving on to Amity Park, they find that Morphoid asteroids rain on the citizens, freeing the Ghost Dog in the process. Goo falls on its head, resulting in him going on a mutated rampage through town. After freeing Dash, Tucker, and Jazz, they fight the Ghost Dog at a power plant, where Ghost Dog crashes into the wall, and goo flies off onto SpongeBob. They gain another piece of the Vessel, and it is again at the lair that Globulous Maximus reveals his identity through SpongeBob. Technus has to flicks SpongeBob's nose to snap him out of the trance when the Krabby Patty smell fails. SpongeBob tells his group that he saw Globulous Maximus, who is the ruler of the Morphoids and will bring doom, gloom, and evil.
Heading to Retroville, the group discovers that the goo has turned Jimmy's girl-eating plant into a monstrous giant, prepareing to eat Cindy whole. After defeating several more Morphoids and freeing Carl, Cindy, and Sheen, they fight the girl-eating plant at the mall. After defeating the plant, SpongeBob gets covered by a glob of goo again. The third piece of the Vessel is retrieved, and SpongeBob states that Globulous Maximus is only a few light-years away from Earth, preparing to send more gigantic Morphoids to destroy it.
Finally, they go to Pupununu Village and find the fourth and final component of the Vessel of Portentia covered in goo and freeing Jibolba and Jeera. SpongeBob pokes the goo to try and free the component, and gets covered in goo. He grabs the component and races to the Mawgu Lair. At the Mawgu Lair, the evil voice of Globulous Maximus informs SpongeBob that he likes him and plans to become him.
The team inserts the pieces of the Vessel of Portentia and then speed towards space. They confront and defeat Globulous Maximus, who is a large asteroid himself with floating arms and a primary eye (along with several non-functioning others). Following Globulous's defeat, the Evil Syndicate betrays the rest of the group to capture Globulous for their own evil plans, taking over the Vessel of Portentia and ejecting the heroes from the robot. Globulous Maximus opens up to the heroes, where he reveals that he was created at the beginning of the universe—the Big Sneeze (a similarity to the Big Bang)—thus making him a huge orange booger. He is destroying worldsbecause he was distasteful of his form and thus took out his anger on others. SpongeBob then tells him to embrace who (or what) he is, and the group throws Krabby Patties in his mouth to make him feel better.
They then wonder how they will stop the Evil Syndicate from taking over the Earth. Globulous states that he has an idea, as he morphs into a huge, orange, and cycloptic version of SpongeBob. Using this form, Globulous and the heroes manage to defeat the Vessel of Portentia on the moon, and it explodes in space, leaving the villains floating around. Globulous returns the heroes to Earth, and says that he will right the wrongs in the universe, taking the moniker "SpongeGlob." The heroes bid him farewell, and SpongeGlob blasts off into space. Meanwhile, SpongeBob sneezes, and the goo finally exits from his body through his many holes. Patrick compares this moment to the beginning of the universe where SpongeGlob was born, while the Wise Old Crab then summons a typical "The End" sign.