For the first time ever, a true collaboration of popular Nickelodeon heroes and villains come together and cross over into multiple Nickelodeon cartoon environments, interacting with each other and working together to solve puzzles in this ultimate Nick gaming adventure. Playable characters from the most popular Nickelodeon shows include SpongeBob SquarePants, The Fairly OddParents, team Rocket Power, Jimmy Neutron and Tak. Nicktoons also marks the videogame debut of new Nickelodeon properties Danny Phantom and Rugrats All Grown Up.

The game opens with SpongeBob discovering that Plankton is taking over Bikini Bottom with gigantic vacuum machines. Goddard exits a portal behind SpongeBob's house, and displays a message to him from Jimmy Neutron. Following Goddard through the portal, he meets Jimmy Neutron, Timmy Turner and Danny Phantom in Jimmy's lab. Jimmy coats SpongeBob with self-regenerating moisture to keep him from dehydrating. Jimmy explains that his latest invention, the Universe Portal Machine, has been copied by Professor Calamitous, whom has formed a Syndicate with Plankton, Vlad Plasmius, and Denzel Crocker, and are already stealing energy from their worlds.

The heroes attempt to teleport into Casper High, but arrive in Vlad's castle, where he reveals that his ghost portal is siphoning energy from the Ghost Zone, and has captured Danny's parents. Vlad knocks the group out and imprisons them in the Ghost Zone Prison. Befriending the Box Ghost, the heroes escape after defeating Walker. Danny leads the heroes to the Fenton Works ghost portal, and meet Sam Manson and Tucker Foley. Upon returning to the castle, the gang destroy the portal's generators. Danny possesses his father and uses his Ghost Gauntlets to pummel Vlad, but ends up escaping. The heroes' then travel to Bikini Bottom, using Jimmy's air gum to breathe underwater. Sandy Cheeks sends them to Jellyfish Fields to meet Patrick Star, but is sucked into a jellyfish-capturing harvester. After destroying the harvesters, the group find themselves on the Flying Dutchman's ship. Danny persuades him to let them go in exchange for bringing back his old crewmates. Upon arriving at the Chum Bucket, they free Patrick and the jellyfish. On the roof, they battle Plankton piloting a gigantic robotic crab to rescue Mr. Krabs, and learn that the villains have been extracting energy to power a Doomsday Machine.

In Dimmsdale, the heroes infiltrate and shut down the power to Crocker's golden fortress. They then head to Fairy World, where they encounter Jorgen von Strangle, free the fairies, and defeat Crocker piloting an exosuit at The Big Wand. The group then return to Jimmy's lab and meet Cindy Vortex. Jimmy then realizes that Calamitous has planted a flea-bot in Goddard to spy on him. The heroes use Jimmy's shrink ray to shrink down to enter Goddard, defeat the flea-bot, and hack it to locate Calamitous' lair. The heroes defeat the Syndicate, and SpongeBob unplugs the Doomsday Machine. With Calamitous in prison, Jimmy gives the heroes each a Neutronic Recaller in case of a future incident, and they part ways.