As depicted in the opening sequence of each episode, the Powerpuff Girls Blossom, Bubbles, and Buttercup were created by Professor Utonium in an attempt to create the "perfect little girl" using a mixture of "sugar, spice, and everything nice". However, he accidentally spilled a mysterious substance called "Chemical X" into the mixture, creating three girls and granting them superpowers, including flight, superhuman strength, superhuman speed, superhuman senses, limited invulnerability, x-ray vision, red heat vision, energy projection, space survivability, and thermal resistance. In the original concept, the accidental substance was a can of "Whoopass", which was replaced by "Chemical X" in the television show.

The three girls all have abnormally large eyes inspired by Margaret Keane's art, and stubby arms and legs, and lack of noses, ears, fingers, flat feet, toes, and necks. McCracken preferred them to look more symbolic of actual children rather than going for a "realistic" look, meaning fewer body parts were needed. Blossom, Bubbles, and Buttercup normally wear dresses that match the colors of their eyes with black stripes, as well as white stockings and black Mary Janes. They individually represent body, mind and spirit, and despite being the same age, they adopt the characteristics of the oldest, middle and youngest child. The closing theme song offers a nutshell description of their personalities: Blossom, commander and the leader. Bubbles, she is the joy and the laughter. Buttercup, she is the toughest fighter.
• Blossom (voiced by Cathy Cavadini) is the self-appointed leader of the Powerpuff Girls. Her personality ingredient is "everything nice", her signature color is pink, and she has long red-orange hair with a red bow. She was named for having spoken freely and honestly to the Professor shortly after her creation, as shown in The Powerpuff Girls Movie. She often behaves as the most level-headed and composed member of the group, with a strong and determined attitude. Her unique abilities include ice breath, microscopic vision, lightning bolts, and advanced intelligence. As the leader, she is a master strategist and apt planner, so she figures everything out and keeps control of the situations.
• Bubbles (voiced by Tara Strong in the series, and by Kath Soucie in the What a Cartoon! episodes) is the "softest and sweetest" of the three. She is the most innocent and childish, as she most enjoys the regular occupations of any child, such as playing games and coloring. Her personality ingredient is "sugar", her signature color is blue, and she has blonde hair in pigtails. Bubbles is kind and sweet, but she is also capable of extreme rage and fights just as well as her sisters. She loves animals and her best friend is a stuffed octopus doll she calls "Octi". She has the ability to both understand multiple languages and communicate with various animals. Her unique powers are projecting powerful sonic scr…

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During Craig McCracken's first year in the character animation program of CalArts, he wanted to produce an animated short film based on a wrestler-type character he made named "El Fuego". In June 1991, he drew three girls with large eyes, visually inspired by the paintings of Margaret Keane, on a small sheet of orange construction paper as a birthday card design for his brother. Looking for some "diversity and balance" in the drawing, he had created a blonde, a redhead, and a brunette. He liked how "cute" they looked and turned them into superheroes, thus replacing the aforementioned wrestler. The following year, the girls starred on McCracken's animated short Whoopass Stew! The Whoopass Girls in: A Sticky Situation. Initially, McCracken wanted to animate all four Whoopass Girls shorts, but only one was produced. McCracken's shorts were selected to be shown at Spike and Mike's Sick and Twisted Festival of Animation in 1994.

While he was working on 2 Stupid Dogs in 1992, McCracken's Whoopass Girls short was picked up for a series by Cartoon Network. The name Whoopass was dropped for inclusion as part of the What a Cartoon! animated shorts showcase. McCracken explained that Cartoon Network executives believed no one would make a children's show with the word "ass" in it, so the title changed to The Powerpuff Girls and the "can of whoopass" was renamed "Chemical X". McCracken's new short, titled "The Powerpuff Girls in: Meat Fuzzy Lumpkins", aired as part the network's World Premiere Toon-In on February 20, 1995. The short was not as popular as Dexter's Laboratory, a project McCracken and former classmate Genndy Tartakovsky (who also directed many episodes of The Powerpuff Girls) worked on together; being the most popular of the shorts, Dexter's Laboratory was the first to be greenlit by the network. Furthermore, McCracken's cartoon did not do well with a test audience composed by 11-year-old boys; "They were saying, 'This is stupid, little girls can't be heroes'", he recalled in 1999. They also found the girls' designs to be disturbing, which caused McCracken to panic and attempt to redesign them in a more realistic style. However, Cartoon Network executive Mike Lazzo convinced McCracken to stay true to his original vision, and allowed him to produce a second Powerpuff Girls short titled "Crime 101", which aired on What a Cartoon! in early 1996. Veteran ABC announcer Ernie Anderson, who narrated the pilot episodes and died of cancer in 1997, was replaced by Tom Kenny when it became a series.

Following the second short, Cartoon Network picked up The Powerpuff Girls for a regular animated series. McCracken said that the show did not go through a large development process, but he was advised to change the name of the three main characters to Pink, Blue and Green, since the network execut…

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In a 2000 Entertainment Weekly review, Marc Bernardin complimented the show on its "spot-on pop-culture acumen" and "unparalleled sense of fun", giving it a warm welcome from earlier "lame" superhero cartoons that he grew up with. Peter Marks of The New York Times noted the show's use of adult humor and pop culture references, declaring it "the sort of playful satire that can appeal as much to a viewer of 37 as 7." Joly Herman of Common Sense Media described the show as a "cute, highly stylized series [that] thrills the senses with its strange characters, funny situations, and lots of lowbrow humor". She went on to say, however, that the show does go from innocent to violent in no time and that there is not much protecting young viewers against the violent undertones. Robert Lloyd of the LA Times said that the series might be "transgressive" based on little violence, but "also cute." In another review, he had called it "perfectly drawn, perfectly written and perfectly voiced."

The show began airing at the height of the "Girl power" trend in entertainment media. The Powerpuff Girls were often compared to the likes of Sailor Moon, Lara Croft, and Buffy the Vampire Slayer, who are also strong and heroic female leads. Craig McCracken argued that he did not create the show to fill a gap in the market encompassed by the "Girl Power" slogan, but that its true vehicle was "good, strong characters" that made for good storytelling. However, he did believe that it gained momentum from being considered a "girl power" cartoon, and that it became successful among boys and girls for the inclusion of action scenes. Terrence Briggs of Animation World Network noted that, "at the very least, Powerpuff Girls works as an interesting comic deviation from the more sexual presences" of other fictional heroines.

TV Guide chose The Powerpuff Girls as No. 13 in a list of the 50 Greatest cartoon characters of all time. IGN ranked the series 18th in its Top 25 Primetime Animated Series of All Time list in 2006. Entertainment Weekly gave it the number one spot in its list of "10 Best Cartoon Network Shows" in 2012.
The Powerpuff Girls series has won two Primetime Emmys, two Annie Awards, and including those four wins, has been nominated a total of sixteen times for various awards.