On a seemingly normal day, SpongeBob and Squidward are on their way to work when huge asteroids started raining down on Bikini Bottom. A huge drop of glob falls on Squidward, causing the top part of his face to turn orange. He then becomes a cyclops of sorts. He then becomes a zombie, chasing SpongeBob around the perimeter of someone's house until Patrick intervenes. Jimmy Neutron then arrives to take them to the Mawgu lair. Soon, the gooey creatures spawning from the asteroids start taking over Bikini Bottom.
SpongeBob and Patrick explore the vast Mawgu lair, where they meet Danny Phantom again, then meet Tak and the new Evil Syndicate composed of Technus, Beautiful Gorgeous, Tlaloc, 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 gooey creatures, identified as 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 received some sort of helmet and a tennis racket, SpongeBob got a bubble blower, Danny received a device that allowed him to partly clone himself, Tak was given a staff, and Zim received a plunger. Meanwhile, on the evil side, Technus received an arm blaster, Plankton was given a hammer that allowed him to grow, Tlaloc received a pouch of magic potions, Dib was given a gun-like balloon launcher, and Beautiful Gorgeous received a heart-shaped bullhorn.
They go through Bikini Bottom, where the group battles an army of Morphoids, free Gary and Patrick from the goo, and finally confront the corrupted Bubble Bass, who has grown to enormous size. They defeat this new menace by feeding him Krabby Patties. SpongeBob is then doused in goo. At the lair, the Wise Old Crab informs them that a huge robot is hidden in the Mawgu Lair, and requires four special components to power it up.
The next world they go to is Zim's town, where GIR has been corrupted by a taco. They manage to free Ms. Bitters, Gaz, and Professor Membrane, then face the corrupted GIR, who has sprouted several mechanical tentacles and has the ability to summon Morphoids from his very being. He soon tires out of attacking the heroes and is then beat up out of being possessed. They retrieve the first piece of the Vessel, while more goo falls on SpongeBob, and at the lair becomes a vessel for the leader of the Morphoids.
They venture to Amity Park, where Morphoid asteroids rain on the citizens, and in the process freeing the Ghost Dog. Not soon after, a blob of goo falls on its head, resulting in him too being corrupted. He goes on a rampage through town. After freeing Dash, Tucker, and Jazz, they fight the ghost dog at a power plant, where the goo falls off of Ghost Dog and onto SpongeBob. They gain another piece of the Vessel, and it is here that he becomes a puppet of sorts for the Morphoid supreme leader, Globulous Maximus who has just revealed himself.
They then head to Retroville, where the goo has turned Jimmy's girl-eating-plant into a monstrous giant and prepares 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 being consumed several times, the team manages to defeat the girl-eating plant and yet another pile of goo falls on SpongeBob. The third piece of the Vessel is retrieved, and Globulous once again talks through SpongeBob.
Finally, they go to Pupununu Village and retrieve the fourth and final piece while Globulous talks through SpongeBob for the fourth and final time.
The team quickly inserts the pieces of the Vessel of Portencia and then speeds toward space, where they confront and defeat Globulous Maximus, who is a large asteroid himself with floating arms and a primary eye. After Globulous is defeated, the Evil Syndicate betrays the rest of the group, taking over the Vessel of Portencia and ejecting the heroes from the robot. Globulous Maximus then opens up to the heroes, where he reveals that he was created at the beginning of the universe, the Big Sneeze, thus making him a huge orange booger. SpongeBob then asks why he was destroying worlds, with Globulous replying that he was distasteful of his form and thus took out his anger on others. SpongeBob then tells him to embrace who he is, and they throw Krabby Patties in his mouth to make him feel better. The group then wonders 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. Depending on the player's actions, one of two endings will occur.
In the "good" ending, achieved by simply defeating the final boss, 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 by 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.
In the "alternate" ending, which requires having a second player take control of the villains' robot on a file that has not already been completed and defeating the first player, Globulous, the villains are shown to have captured Globulous in a giant glass jar, with the credits rolling immediately afterwards.
Jimmy Neutron, Danny Phantom, SpongeBob SquarePants, and Patrick Star were the only characters that appeared in all four games, while Danny and SpongeBob were the only characters playable in all four games.
This was the second game in the series since Nicktoons Unite where Patrick Star is not a playable character.
This was the third Nicktoons crossover game to feature Plankton.
If the player exits the hub or the loading is not complete, the game file will become corrupted.
Plankton is the only original syndicate member from the first game.
This was the only "NickToons Unite!" game where SpongeBob does not use his karate gear as his weapon.
Although, his glove can be seen as a power-up.
This was the second time in a row that GIR appears in a Nicktoons Unite sequel.
The goo in the game is similar to the Nickelodeon logo goo.
This is the last SpongeBob game to have a PlayStation 2 release, as PS2s and PS2 games are no longer manufactured.
In the Bikini Bottom levels, Bubble Bass is heading towards the Krusty Krab, at the end of the first level SpongeBob and Beautiful Gorgeus are seen at the Chum Bucket, it is unknown why they did not just cross the street to get to the Krusty Krab.
SpongeBob and Plankton have many of the same lines in the game.
In the first Bikini Bottom level, some of the boats say "Y2K Shell."
In the Bikini Bottom hub, there is a strange texture around and on top of Patrick's home. The texture seems to be a mix of eyes, Patrick's shorts, and Patrick's skin.
This game takes place after the episode "Plankton!" because SpongeBob knows Karen.
The box art and disc art use the 2008 SpongeBob logo, but the game's title screen uses the old one.
This is the only PS2 game to use the 2008 SpongeBob logo.
The PS2 and Wii versions have the same gameplay, while the Nintendo DS version has its own gameplay style.
The game continually switches between day and night in some of the levels. When SpongeBob and Beautiful Gorgeous travel to Bikini Bottom, it was day time. But when Jimmy and Plankton were at the Bikini Bottom Dump it was night.
In the 2nd Amity Park level, there is a glitch from when the player pulls the three Switches the fan won't work and the player will get stuck on the level.
In the second Bikini Bottom level:
In the dump:
Eugene H. Krabs' mattress is seen even though he supposedly took it back home after "The Lost Mattress." Although this could have been someone else's mattress, it is unlikely because it had money in it and most people, other than Mr. Krabs, don't put their money in a mattress.
The player(s) can see (and go into) Mr. Krabs and Plankton's childhood hangout spot from the episode "Friend or Foe," but, it has a hole at the top of it, this is an error because in the real version of the story neither Plankton nor Mr. Krabs were shot out of the roof. When the player(s) go(es) inside it looks different than from the episode.
When the player(s) get(s) off the bus the player(s) can see the characters appear right before the bus does to let them off.
In the Theater, when the player(s) enter the bathroom and enter one of the stalls a fish runs out and runs off to the wall, he is just running in place at the wall.
During the cut scene before the second Bikini Bottom level, Plankton says that the Chum Bucket is in danger, but, the Chum Bucket is not seen in the next level.
In the first Amity Park level, when the player(s) go to the top of Casper High and look at the baseball field, the giant morphoid monster that appears later is not there.
In the first Bikini Bottom level, after the player(s) pass(es) the 3 houses, there is a sign that says "Bikini Bottom 50 miles." This is inaccurate because SpongeBob, Patrick, and Squidward live in Bikini Bottom.
In the first two Bikini Bottom levels, in the gameplay, the buses don't have the "periscope."
In the second Bikini Bottom level, the Reef Cinema is in town, but in the series, it has a path leading to the cinema, which separates it from the town.