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June Foray provided the voice of Madame Argentina in the episode, "I See a Funny Cartoon in Your Future." In honor of this, the episode was made to feel like an episode of "Rocky & Bullwinkle." In fact June Foray the voice of Madame Argrentina and Tom Kenny the voice of the Mayor and the Narrator later stared in Rocky and Bullwinkle (2014) which was the last time they worked together before Foray's death in July 2017. Tara Strong the voice of Bubbles later replaced Foray as Rocky in The Adventures of Rocky and Bullwinkle (2018) which debuted 20 years later after this show's debut.
Cartoon Network asked for a seventh season of the series. Creators and producers Craig McCracken and Chris Savino felt that six was enough.
George Jetson of The Jetsons (1962) occasionally appears in the background flying in his space car as Blossom, Bubbles, and Buttercup are in flight to a rescue.
The devilish, demonic rival named is referred to as "Him" because the producers thought the Devil or Satan or any other name would be too controversial for a kids' show.
All of the character designs are based around curves with exception of one. Professor Utonium's design is based entirely around straight lines and sharp angles.
The Powerpuff Girls (1998) names were based on Fauna, Flora, and Merryweather from the popular Disney movie, Sleeping Beauty (1959).