On August 24, 2020, a live-action television series based on The Powerpuff Girls was announced to be in development at The CW. According to Variety, it would depict Blossom, Bubbles and Buttercup as "disillusioned twentysomethings" resentful at losing their childhood to fighting crime and faced with the choice of reuniting "when the world needs them more than ever." The project, produced by Warner Bros. Television Studios, was being written by Heather Regnier and Diablo Cody, who were also serving as executive producers with Greg Berlanti, Sarah Schechter and David Madden.[89] Craig McCracken was not involved; however, he declared his liking of Berlanti's superhero shows and admitted he was "curious" to see what they would do with their adaptation.[90] Genndy Tartakovsky, who directed and produced several episodes of the original show, also expressed a similar sentiment, suggesting that the idea was "strong" and could work if there's "good people attached to it".[91][92]

A pilot was officially ordered on February 9, 2021, and Maggie Kiley was hired as the director.[93] Variety later reported that Chloe Bennet, Dove Cameron and Yana Perrault were cast as Blossom, Bubbles, and Buttercup.[94][95] On March 30, 2021, following the title change to Powerpuff, Donald Faison was cast in the role of Professor "Drake" Utonium.[96] On April 1, Nicholas Podany was cast as Joseph "Jojo" Mondel Jr., the son of Mojo Jojo.[97] On April 7, production on the pilot began.[98] On April 9, Robyn Lively was cast as Sara Bellum and Tom Kenny was confirmed to be reprising his role as the Narrator from the original series.[99] On May 24, The CW announced that the pilot would be reworked off-cycle, with the cast and crew remaining on board.[100] The script was leaked later that day, to overwhelmingly negative reviews on social media. Mark Pedowitz, the head of The CW, stated that the script would be largely rewritten.[citation needed] On August 11, Bennet dropped out of the project due to scheduling conflicts.[101] In May 2022, it was said to be in "some stage" of redevelopment.[102] However, on May 18, 2023, The CW announced that the series had been cancelled by its new majority owners, Nexstar Media Group, and that the rights had been returned to Warner Bros.[103] On July 5, it was reported that the series was no longer in development at Warner Bros. Television.