The Powerpuff Girls are three super-powered little girls out to save the world before bedtime. Created when one of Professor Utonium's attempts to create "perfect little girls" mixing sugar, spice, and everything nice was accidentally infused by the naughty lab monkey Jojo with super-powerful Chemical X, the Powerpuff Girls, Blossom, Bubbles, and Buttercup, use their unique abilities to protect the city of Townsville from monsters and villains such as Mojo Jojo, Fuzzy Lumkins, Him, Princess Morbucks, the Gangreen Gang, and others.
Powerpuff Girls Z, a magical girl anime series loosely based on the original series, was released in Japan much later. While the character design of the girls remained similar, much of the backstory and story progression diverged from the original cartoon.
In FusionFall, the Powerpuff Girls are now in middle school. A number of characters from the cartoon are present: these include the heroines themselves, Professor Utonium, the Mayor of Townsville, and major antagonists Him, Mojo Jojo, Princess Morbucks, Fuzzy Lumkins, the gender-flipped Rowdyruff Boys, and the Gangreen Gang, with their leader, Ace. Many areas are based on or inspired by the show, including Pokey Oaks, Townsville Center, Townsville Park, City Hall, Mojo's Volcano, and Morbucks Towers.
- The home of the Powerpuff Girls can be found in Pokey Oaks South.
- Monkey Minions are an NPC group based of the show and serve as minions of Mojo Jojo. A certain number of them serve as the Monkey Skyway system which helps move players around to another area for a fee.
- There are fountains in Townsville Park that have a statue of Ms. Bellum, the Mayor's secretary, though true to the show, the portion that would show her face is broken off and missing.
- During the Thanksgiving event, the Blowfish appeared as a wandering NPC in Pokey Oaks South. For the Mother's Day Event, the Mother of all Blowfish appeared in Candy Cove.
- Princess Morbucks is locked up in one of the Ice King's Dungeons for the Ice King Invasion having been one of the princesses held prisoner by the Ice King.
- At Camp Kidney, there is an agent named Agent McCracken, a reference to the show's creator, Craig McCracken.
- At the comic book shop in Pokey Oaks South, you can see the Powerpuff Girls in some of the comic books on display.