The show is set mainly in the city of Townsville, USA. The cartoon always tries to keep different ideas within each episode with some small tributes and parodies thrown in. Episodes often contain hidden references to older pop culture (especially noticeable in the episode 'Meet the Beat Alls', which is a homage to the Beatles). In addition, the girls have to deal with the normal issues that young children face, such as sibling rivalries, loose teeth, personal hygiene, going to school, bed wetting, or dependence on a security blanket. The plot of an episode is usually some humorous variation of standard superhero and tokusatsu shows, with the girls using their powers to defend their town from villains and giant monsters.

The show revolves around the adventures of three kindergarten-aged girls with an array of various superpowers: Blossom (pink), Bubbles (blue), and Buttercup (green). The series has been nominated for six Emmy Awards, nine Annie Awards, and a Kids' Choice Award during its run. Various spin-off media include an anime, three CD soundtracks, a home video collection, comic books, a series of video games, a 2016 reboot series, and an upcoming second reboot, as well as various licensed merchandise.

A total of 78 episodes were produced, in addition to the two pilots, a Christmas special, the film, a tenth anniversary special, and a special episode in computer animation. The Powerpuff Girls aired on Cartoon Network for six seasons, three specials, and a feature film, with the final episode airing on March 25, 2005. Network executives gave McCracken the greenlight for a full series, which debuted as a Cartoon Cartoon on November 18, 1998. Following the name change to The Powerpuff Girls, McCracken submitted his student film to Cartoon Network, who aired the series' refined pilot, 'Meat Fuzzy Lumpkins', in its animation showcase program World Premiere Toons on February 20, 1995, along with its follow-up, 'Crime 101', on January 28, 1996. While attending his second year at CalArts in 1992, McCracken created a short film, Whoopass Stew!, about a trio of child superheroes known as the Whoopass Girls, which was only shown at festivals. They live in the fictional city of Townsville with their father and creator, a scientist named Professor Utonium, and are frequently called upon by the city's mayor to help fight nearby criminals and other enemies using their powers. The show centers on Blossom, Bubbles, and Buttercup, three kindergarten-aged girls with superpowers. The Powerpuff Girls is an American superhero animated television series created by animator Craig McCracken and produced by Hanna-Barbera (later Cartoon Network Studios) for Cartoon Network.

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