Things have gone bad in the city of Townsville due to crime and general apathy on the part of most every citizen. That is, except for Professor Utonium (voice of TOM KANE), a forward-looking man who thinks back to a sweeter time. Accordingly, he sets out to invent some sweet little girls, but an outside component - Chemical X - accidentally spills into the mix.
The yield results in Blossom (voice of CATHERINE CAVADINI), Bubbles (voice of TARA STRONG) and Buttercup (voice of E.G. DAILY), three diminutive girls with huge heads, enormous eyes - from which they can shoot lasers - and the ability to fly.
The Professor is as giddy as any new father, but concerned a bit about the girl's superhuman powers. Thus, when elementary school teacher Ms. Keane (voice of JENNIFER HALE) tells him that they've been acting normal on their first day of school, he's relieved. Yet, when the girls are taught the game of tag, thinks quickly get out of control as they become overexcited and unintentionally cause a tremendous amount of damage to the city. Even so, the Professor still loves them, but does tell them that they can't use their superpowers anymore outside the house.
The next day, the once popular girls are surprised to discover that they're now unwelcome outcasts, while Townsville's Mayor (voice of TOM KENNY) has the Professor arrested for their behavior. On their way home, the downcast girls meet fellow outsider Jojo (voice of ROGER L. JACKSON), an escaped primate from Utonium's lab, who commiserates with them about being hated for being special and unique.
Soon he has them agreeing to help build a "Help the Town and Make It a Better Place" machine that he promises will win back the city's favor for them. Little do the girls know, however, the Jojo has included them in a dastardly plan of infusing the local zoo's primates with superpowers and then ruling over them, the city and its citizens as Mojo Jojo.
Once they realize the havoc they have wrought, the girls must decide what to do to make things right as well as how they're going to take on the power-hungry primate and his out of control minions and save the city.