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One morning, when SpongeBob SquarePants goes out of his house, he sees that Plankton has taken over Bikini Bottom and used multiple tank-like vacuums to suck away all of the town's civilians. He sees Goddard coming out through a portal and receives a message from Jimmy Neutron. He follows Goddard through the portal to Jimmy's lab and meets Jimmy Neutron, Danny Phantom, and Timmy Turner. Since SpongeBob is an aquatic being in need of water, Jimmy uses one of his few non-backfiring inventions to coat SpongeBob in a coat of self-regenerating moisture. 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 Denzel Crocker to his dimension. They formed a Syndicate and proceed to steal energy from all the worlds. Since our heroes do not know where Calamitous' lair is, they start with saving all of their worlds first.
Danny suggests that they go to his world first, so Jimmy uses the portal machine to take them to Casper High in Amity Park. However, much to their surprise they end up in the throne room of Vlad's new castle, which he built over Casper High. Vlad reveals that he is using his personal ghost-portal to syphon ghost energy from the Ghost Zone to help further the Syndicate's ultimate plan. Also, as a precaution, Vlad had captured (unknown to the rest of the good guys) Danny's parents. As usual, Vlad tries to win Danny over to his side, but Danny rebuffs the offer as usual. Confident, Vlad knocks them unconscious and imprisons in the Ghost Zone Prison now under his control. Befreinding the imprisoned Box Ghost, the Nicktoons escape their holding area and proceed onwards with Danny phasing through the walls and deactivating the machines that keep physical beings from escaping. However, at the exit, the meet the Warden of the Prison, Walker, who is not too happy with their prison break. Knocking Walker out, Danny leads the heroes to the ghost-portal leading to the basement of Fenton Works, where he quickly lies that he has no relation to the Fentons and that they are the experts in Ghost Hunting. They exit Fenton Works and encounter Danny's friends, Sam and Tucker, who tell them some of the people in Amity Park have been possessed by the ghosts released from Vlad's portal. The Nicktoons use Danny's ghost powers to drive the possessors out and beat the ghosts senseless. Taking a shortcut to Plasmius' castle through the Amity Park Graveyard, the Nicktoons arrive and 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 with the help of the 'Ghost Gauntlets' Jack Fenton (Danny's dad) was wearing while Danny possessed him to gain the upper hand. While Jack and Maddie recover from the trance Vlad placed them in, Vlad gloats to the heroes that the Syndicate is building something and have sufficient ghost energy to help power it before fleeing his world.
Next, our heroes go to Bikini Bottom to fight Plankton (with Jimmy, Danny and Timmy using Jimmy air gum to breathe underwater). 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 to 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 (minus SpongeBob as he has had to put up with his annoying antics before). Luckily, the Dutchman decides to free them after they bring back his old crew (Danny lightly mentioned he's good at telling ghosts what to do). When the Nicktoons arrived to the Chum Bucket (now heavily modified into a grand castle next to the factory), they free Patrick, then free all the Jellyfish by opening the emergency vents. Later, they went up to the top of the Chum Bucket, where they face Plankton (using a robot crab)and rescue Mr. Krabs (who was being tortured by having money taken and given to him). The Nicktoons find out that the villains are extracting energy for a Doomsday Device and that Mr Crocker is still supplying power to it from Dimsdale.
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. (Since Jimmy has already met and misunderstood the existence of Fairies, he explains wrongly that they are in a computer simulation) Jorgen explains that Crocker is extracting the magic from the Big Wand (which powers the fairies magic wands)to feed the Doomsday Machine. After freeing the fairies, they go to The Big Wand, where they defeat Crocker (who used the big wand's magic to give himself a powerful battle suit and limited magic). SpongeBob and Danny deduce that the villains are retreating to Retroville in Jimmy's world to regroup after being defeated. Timmy then assures his new friends that everything will be okay now that the Big Wand is giving fairies back their full magic. He tries to wish the bad guys into jail and the Doomsday machine dismantled. However, Wanda says Da Rules only allow changes to Dimsdale's dimension, disappointing the heroes.
The Nicktoons return to Retroville to think of a new plan, where Jimmy finds Cindy in his lab and he also receives a message from Calamitous (still having trouble finishing things) that they have almost finished the Doomsday Machine and the Nicktoons cannot stop them. After SpongeBob notices that Goddard has fleas, Jimmy says that Goddard does not 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 Jimmy explains that the others need to gain Goddard's trust before they can receive clearance and proceed(Jimmy already had clearance). Danny, Timmy and SpongeBob gain Goddard's trust by helping him in his memory, as Jimmy programmed Goddard to act like a normal dog. 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. Overconfident, the Syndicate declares they will destroy Retroville's dimension as a demonstration of their power. However, the heroes beat the Syndicate but they see that the Doomsday Device is still counting down to destroy Jimmy's universe and it cannot be stopped. Luckily, SpongeBob unplugs the Doomsday Machine and saves the universe. Calamitous laments that he forgot a back-up system.
After putting Calamitous in jail and the trapping the villains, 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 anytime he likes, but then he said he should get going, so he will not be charged by Mr. Krabs for wasting his time (even though SpongeBob and the others saved his life from Plankton, whose imprisonment is unknown. Though most likely, he's in SpongeBob's pocket), Danny gave Jimmy a copy of the Fenton Thermos (since the original thermos had Vlad trapped inside, Danny used Jimmy's now non-glitched Matter Duplicator to make a copy), which Jimmy says may help him figure out what "those phantasmol images really were" as he does not believe in ghosts, then Timmy thanked Jimmy for lending him his Hyper-Cube for holding Crocker until Timmy and his fairies get back to Dimmsdale as Cindy waves him off. After this, Jimmy says a familiar line: "Cindy, get out of my lab!"
In console version player can play with three computers and no other human players, or with a friend or two with the remaining computer(s). One can switch abilities, which have multiple uses. There are also things only a certain character can do. For example, SpongeBob is needed to use Bubble Bombs to blow up a pillar, Danny is needed to use Ghostly Wail on some glass, Timmy is needed to use Freeze Glove to freeze some water, or Jimmy has to shoot down some things with his Neutron Flare.
Goddard can be found in all four worlds (and oddly enough, inside himself) so he can upgrade the players weapons and abilities.
The game received critical acclaim, with the Gamecube version gaining a score of 9.4 from the IGN community, while the PS2 version got a 9.7. The GBA version was positive, receiving a 8.0. The DS version got a 8.0. Gamespot called the game "A game that changed the gaming industry forever. This game is a must have". Joystiq gave the game a 5 stars out of 5 saying "The game is perfect, no flaws, great story, and a perfect crossover". The game is often considered one of the greatest video games of all time.