Both versions of the game are completely different from each other.
The game begins with a cutscene of Ms. Fowl and some students on a field trip to a museum tour. Jimmy, appearing bored, and yearning for variety, shouts "CAN'T ANYTHING BE DIFFERENT?!"
When then cut to another dimension, where Jimmy Negatron, an evil version of Jimmy programs his dimensional portal so that he can complete his evil objectives.
Now cutting back to the museum, Cindy then challenges Jimmy by saying that his theory on time travel is "pure genius". He then decides to impress her by programming the portal in the museum to make himself and Goddard teleport 50 years backwards. But Negatron then changes the teleporting coordinates to two cages in his laboratory. Jimmy and Goddard are then teleported to the cages. Negatron then introduces himself to Jimmy. Neutron inquires what exactly Negatron's plan is. Negatron reveals that his plan is to modify Retroville to his evil liking. As he leaves, he tells his robot henchman, Hermin to guard Jimmy and Goddard.
Negatron enters Jimmy's dimension, much to the confusion of Cindy, and then offers her a modified version of the Purple Flurp, now dubbed Black Flurp.
Back in Negatron's dimension, Jimmy tricks Hermin into letting him and Goddard out of the cage by making him think he is Negatron, and then orders Hermin to play in the broom closet. Neutron, now freed from the cage, creates a water balloon launcher and teleports from the dimension, only to be transported to a ravine where there is a tall wall of water coming to sweep him away.
Jimmy escapes from the ravine and into a warehouse. Jimmy, seeing submarine parts scattered across the floorboards, decides to put them together and ride the submarine back to Negatron's lab to reroute the teleportation coordinates, but the door to the crane is locked. So, Jimmy goes inside the warehouse to make his way to the crane.
After assembling the sub pieces together, he pilots the sub into the ocean, where there is a door leading to Negatron's lab, but it requires a crystal to unlock. There being another door requiring a key to unlock, Jimmy gets the crystal and the key, making his way to Negatron's lab. Jimmy rewrites the portal coordinates, then gets back to Retroville. Hermin, now overpowered will anger, transports to Jimmy's dimension to find him and bring him back to Negatron's dimension.
Back at the museum, Jimmy loads up a backup version of Vox and finds out that Negatron has been causing trouble in Retroville.
The following three bosses/missions can be done in any preferred order.
When Negatron offers Carl a Black Flurp. Carl drinks the Flurp, becomes gigantic, and gains an overwhelming hunger. After using a rocket ship equipped with a food launcher, Jimmy feeds Carl and shrinks back to normal.
Ms. Fowl takes the students to the Egyptian exhibit of the museum, where Negatron traps Fowl in a sarcophagus on the top of the pyramid exhibit. Jimmy gets all the way to the top of the pyramid to save Fowl.
Meanwhile, Negatron teleports Jimmy's parents into the Egyptian exhibit of the museum, where he traps them in two sarcophagi in a cage Jimmy gets to the museum, and in order to free them, he has to find two keys.
When finding the first key, he encounters mummy-bots placed in the exhibit by Negatron which he defeats with his water balloon launcher. After finding the second key, Jimmy then frees his parents.
When Libby approaches Jimmy's lab's entrance to talk to Jimmy, a hacked Vox then teleports Libby inside the system. Jimmy is transported inside as well. Jimmy loads up a bug sprayer, to destroy the bugs inside Vox's system. After rescuing Libby, Jimmy proceeds to explore more of the damage Negatron has caused.
It turns out that Negatron has time-traveled back to Halloween night, and has equipped himself with an energy shield. Jimmy uses a Neutron Field Disruptor to destroy the energy shield. After defeating Negatron, he then time-travels to Christmas, and then to Independence Day. Meanwhile, in the present day, Hermin, now dubbing himself the "Herminator", mistakes Jimmy's mailbox for Jimmy himself, and he takes the mailbox instead.
Jimmy gets to the Flurp factory to stop Negatron from making any more of the Black Flurp. But The Herminator teleports to the factory to get Jimmy and bring him back to Negatron's lab. Jimmy builds a Burpzooka and defeats the Herminator. Jimmy then destroys all the Black Flurp bottles, but Negatron has not yet been defeated!
It turns out that Negatron has made the dinosaurs in the museum into robots as they wreak havoc throughout Retroville. Jimmy equips his rocket with the water balloon launcher and shoots the dinosaur robots, making them short out.
Negatron goes back to his dimension, but finds out that Neutron changed his return coordinates and because of Hermin continually mistaking Jimmy Neutron and Jimmy Negatron, he has trapped Negatron in the cage. And so the game ends.
- Hermin's nickname is a parody of The Terminator.
- Negatron was going to be a villain on the show and his name was supposed to be "Nummie Jetron". That role was given to Evil Jimmy.
- This is the only video game to use Cindy's design from the show.