The Powerpuff Girls must battle enemies in a variety of settings in order to reclaim Chemical X and track down Mojo Jojo. Players can choose from ten playable characters, which consist of the three Powerpuff Girls and seven villains (Ace, Big Billy, Fuzzy Lumpkins, HIM, Mojo Jojo, Princess Morbucks, and Sedusa).
In the story mode, players can pick up objects and throw them at an enemy to decrease their opponents health meter. They can use superpowered attacks by collecting vials of Chemical X. For the PlayStation edition, all three Powerpuff Girls were given an additional special move. If the player successfully defeats the enemy in two out of three rounds, they move to the next enemy location.
Players can play the story mode or can battle against a friend in a head-to-head battle.
In Simulator Mode, people can fight as a Powerpuff against a villain or a villain against another villain.