The series is a reboot of the original Powerpuff Girls created by Craig McCracken, developed instead by Nick Jennings, an art director on SpongeBob SquarePants and Adventure Time, and Bob Boyle, who had previously worked on Clarence, Yin Yang Yo!, Wow! Wow! Wubbzy!, The Fairly OddParents and Danny Phantom.

Craig McCracken did not work on the reboot; he stated on Twitter that Cartoon Network executives had considered bringing him back, but his contract with Disney Television Animation prevented him from doing so.

The three lead roles were recast with new voice actors Amanda Leighton, Kristen Li, and Natalie Palamides, replacing original actresses Cathy Cavadini, Tara Strong, and E. G. Daily.

Producer Nick Jennings revealed that the team had considered bringing back the original voice actors but ultimately decided that recasting the roles would bring new energy to the series.

Several supporting actors reprised their original roles, including Tom Kenny as the Mayor and narrator, Tom Kane as Professor Utonium and Him, Roger L. Jackson as Mojo Jojo, and Jennifer Hale as Ms. Keane (though not as Princess Morbucks).

Before the recast was even fully public, original actresses Cavadini, Daily and Strong expressed displeasure; Tara Strong called the decision 'a stab in the heart' on Twitter, though she later said in 2017 she held no ill will and gave the new show her blessing.

A one-shot leaked footage on Cartoon Network Russia revealed the addition of a new, fourth Powerpuff Girl named Bliss, before the character was officially confirmed in the five-part special 'The Power of Four'.

The reboot dropped the classic villainess Sedusa, replacing her with a new character, Bianca Bikini, and also wrote out the character Ms. Bellum, changes that drew criticism from fans and critics who felt it undermined the show's feminist message.

The season one episode 'Horn, Sweet Horn' drew significant media criticism for its handling of transgender themes, with commentators comparing its portrayal of a transformed character as a monster unfavorably, and one writer later said the implication was unintended and blamed the episode's advertising.