One morning, when SpongeBob goes out of his house, he sees that Plankton has taken over Bikini Bottom and used multiple tank-like vacuums to suck all the town's civilians. He sees Goddard coming out through a portal and receives a message from Jimmy. He follows Goddard through the portal to Jimmy's lab and meets Jimmy Neutron, Danny, and Timmy. Jimmy tells his interdimensional guests about his new invention, the Universe Portal Machine. As he says, it allows people to travel to other worlds. But Prof. Calamitous has been spying on him, stole his idea and created his own Portal Machine. With it, he brought Plankton, Vlad Plasmius, and Mr. Crocker to his dimension. They formed a syndicate and proceed to steal energy from all the worlds. Since our heroes don't know where Calamitous' lair is, they start with saving all of their worlds first.
They go to Amity Park first and find Vlad. Vlad reveals that he uses his ghost-portal to steal ghost energy from the Ghost Zone. Vlad has also captured Danny's parents. Then, he sends the heroes to the Ghost Zone Prison. The Nicktoons survive in the prison, and defeat Walker. They break out of the prison through a portal and end up in Fenton Works. They see many Amity Park civilians possessed by ghosts, but manage to push them out. The Nicktoons go to the Amity Park Graveyard, which is a shortcut to Plasmius' castle. When they go in, Jimmy realizes that there are generators that help Vlad keep the portal open. They find the generators, and destroy them, shutting off the portal. When they find Vlad, the Nicktoons defeat him and save Jack and Maddie Fenton without them noticing the Nicktoons. They also find out that the Syndicate is building something.
Next, our heroes go to Bikini Bottom to fight Plankton. They meet Sandy, and follow her to The Krusty Krab. Sandy tells the Nicktoons that they should find some guards which should help them find Plankton and the Jellyfish Factory. Fortunately, they found the guards. Sandy then explains that Plankton uses the harvesters capture various Jellyfish, and is extracting power from their sting in the factory. Plankton also captured Mr. Krabs. Sandy told the Nicktoons that they must go into the Jellyfish Factory and free all the Jellyfish. After Timmy asked if they have any secret agents (since he thought that it's like a spy movie), Sandy said that they have an agent in Jellyfish Fields, who reveals to be Patrick, but he's been captured by a Jellyfish harvester. After destroying all the harvesters, the Nicktoons go to the factory, but during the journey, they find themselves on the Flying Dutchman's ship and the Flying Dutchman is going to make them his new crew for all eternity. Luckily, the Dutchman frees them after they bring back his old crew. When the Nicktoons arrive to the Chum Bucket, they free Patrick and all the Jellyfish by opening the emergency vents. Later, they went up to the top of the Chum Bucket, they beat Plankton and rescue Mr. Krabs. The Nicktoons find out that the villains are extracting energy for a Doomsday Device.
In Dimmsdale, the Nicktoons see Crocker has made the fortress made of gold. They also find a rainbow of pure Fairy Magic from the Fairy World that is ending there, so they go in. After they re-activate the prisms, they get transported to Fairy World, where they meet Jorgen Von Strangle. Jorgen explains that Crocker is extracting the magic from the Big Wand to feed the Doomsday Machine. After freeing the fairies, they go to The Big Wand, where they defeat Crocker. Danny figured out that every time they beat their enemies, they're running away, which was a part of a plan.
Finally, the Nicktoons return to Retroville, where Jimmy finds Cindy in his lab and he also receives a message from Calamitous that they've almost finished the Doomsday Machine and the Nicktoons can't stop them. After SpongeBob notices that Goddard has fleas, Jimmy says that Goddard doesn't get the fleas. Then, he figured out how Calamitous could spy on him; he was using a flea-bot inside Goddard. So the Nicktoons shrink themselves down and go to Goddard's stomach. They beat a lot of mini flea-bots throughout Goddard, and Danny, Timmy and SpongeBob gain Goddard's trust. They go to Goddard's head and beat the giant flea-bot. Jimmy used the flea-bot's circuitry and locate Calamitous' secret lair, which is situated under an old warehouse. When they get to Calamitous' Doomsday lab, they find The Syndicate in a wheel-like machine which shields them. They beat the Syndicate but they see that the Doomsday Device is still counting down to destroy the universe and it can't be stopped. Luckily, SpongeBob unplugs the Doomsday Machine and saves the universe.
After putting Calamitous and Plankton in jail, the Nicktoons said themselves goodbye, but before they went, Jimmy gave them the Neutronic Recallers in case of another event like this. SpongeBob said that Jimmy can visit him any time he likes, but then he said he should get going, so he won't be charged by Mr. Krabs for wasting his time (even though SpongeBob and the others saved his life), Danny gave Jimmy a copy of the Fenton Thermos (since the copy Thermos had Vlad trapped inside, Danny used Jimmy's Matter Duplicator to make a copy), then Timmy thanked Jimmy for lending him his Hyper-Cube for holding Crocker until Timmy and his fairies get back to Dimmsdale. After this, Jimmy says a familiar line: "Cindy, get out of my lab!".
In the console versions, a player can play by him/herself with three CPU's, or have up to three friends play along. In single player, the person playing can switch between the four characters at any time in the game by using the Directional Pad (that little pad thing that looks like a plus(+) sign that's either over the left analog stick for the PS2 controller, or under the grey Control Stick on the GameCube controller). Every character's health and Special Ability Power (SAP) is represented by the two combined arrow-point shaped bars near the character's face icon on the bottom left corner of the screen. In single player, depending on where the arrow is pointing, that's the direction to push on the D-pad to switch to the corresponding character. The green bar represents health, the purple means SAP. A character's health lowers when they take damage from things such as enemies. When a character's health lowers to an especially low degree, the character says they need help, and the character's face icon changes to a more worried and tired icon that flashes red. If a character's health depletes completely, then that character dies, not effecting the rest of them, but costing that character a life. If a single character lose all their lives, the player gets a game over, because all the levels in the game have sections that require the now dead character's special powers. More health can be earned by picking up the green orbs of it that enemies drop when you defeat them. There are certain tasks that only a certain character can do, and performing these special abilities will deplete the character's SAP meter. For example, SpongeBob is needed to use Bubble Bombs to blow up seemingly breakable walls and pillars, Danny is needed to use Ghostly Wail to shatter glass, Timmy is needed to use Freeze Glove to freeze water instantaneously, and Jimmy has to shoot down objects with Neutron Flare. If a character completely depletes their SAP, they can no longer perform that ability (or the rest of their special abilities) until more SAP gradually comes back over time, or the player collects the purple orbs of it enemies drop when they're defeated, exactly like how recovering life works. There are two kinds of fighters to play as. SpongeBob and Danny both use their hands to attack, while Timmy and Jimmy send out projectiles. SpongeBob and Danny are better for defeating enemies faster because they both use close-quarters combat, but are more likely to get hit if there's a large crowd of enemies. And while Jimmy and Timmy use projectiles so they can damage enemies from a farther distance allowing them to stay out of range from enemy attacks, it will most likely take longer to kill them due to the projectiles lack of strength and speed.
Goddard can be found in all four worlds so he can upgrade the players weapons and abilities.