Eleven-year-old boy genius Jimmy Neutron resides in the vibrant town of Retroville alongside his loving parents, Judy and Hugh, as well as his trusty robot dog, Goddard. Jimmy's circle of friends includes the lovable yet overweight Carl Wheezer and the energetic Sheen Estevez. However, he often finds himself butting heads with his intelligent and teasing classmate, Cindy Vortex, who frequently mocks him for his petite size.
When Jimmy ambitiously launches a communications satellite, hoping to make contact with extraterrestrial beings, he accidentally crashes his makeshift rocket, causing havoc at home and upsetting his mother. The following day, in anticipation of the much-awaited grand opening of Retroland, an amusement park, Jimmy, Carl, and Sheen are persuaded by the popular Nick Dean to sneak out for a night of adventure. However, Jimmy's plans are thwarted when his mother grounds him after a mishap involving his jetpack.
Determined to join his friends, Jimmy concocts a plan using his shrink ray to sneak out, leading to a night filled with excitement at Retroland. Meanwhile, unbeknownst to the children, Jimmy's satellite message has attracted the attention of the Yolkians, a peculiar race of egg-shaped aliens from the planet Yolkus. Their leader, King Goobot, finds a picture of Jimmy’s parents in the transmission, marking the beginning of a frantic chain of events. The Yolkians invade Earth, abducting all the adults in Retroville - except for Jimmy's teacher, Miss Fowl, who gets shrunk down due to Jimmy's invention.
Awakening to find their parents missing, the children initially celebrate their newfound freedom, but soon realize how much they crave their families. Understanding that the Yolkians are responsible, Jimmy takes charge and recruits his friends to build rocket ships using the attractions at Retroland, determined to rescue the abducted parents.
After navigating through a dangerous meteor shower and camping on an asteroid, they finally reach the planet Yolkus. Here, they discover the parents are being controlled by mind-control helmets. When Goobot captures Jimmy while he attempts to save his father, he reveals that Jimmy inadvertently led them right to Earth for their sinister sacrificial plans involving Poultra, their god.
In a state of despair, Jimmy finds himself locked away with the other children, but Cindy steps up and reminds him of their need for his brilliance and leadership. With a clever use of a cellphone belonging to Cindy's friend, Libby Folfax, Jimmy contacts Goddard, who heroically frees them from captivity.
The climax unfolds in the Yolkians' Colosseum, where Poultra, a massive three-eyed alien chicken, is set to make an appearance. As Goobot prepares to use a mind-control device against their parents, Jimmy courageously leads the children in a revolt against the guards while Sheen makes a daring retrieval of an escape vessel.
With sheer determination, they manage to escape Yolkus, but not without attracting Goobot's wrath, who sends a fleet after them. However, using his shrink ray, Jimmy grows to a gigantic size to confront Goobot, ultimately destroying his ship. Despite the chaos, Jimmy finds reconciliation with his parents, openly admitting that intelligence can only go so far without love and support.
In a whimsical mid-credits scene, a miniature Miss Fowl is seen riding on an apple worm named Mr. Wiggles, making her way to the cafeteria, ensuring the charm of Retroland continues even in the aftermath of their grand adventure.
