The Powerpuff Girls move along with their father/creator, , to Megaville. At first, the girls don't like that they moved to a new city and have to meet new people. The girls are also transferred to a new school, Megaville Elementary, where their teacher, Miss Meryl, has them introduce themselves; the girls talk about their superhero abilities, but none of the students in class (except one student) believe them and starts laughing at them. During recess, a boy in a lab coat walks up to them and apologizes on behalf of the rest of the class. He tells them he believes them about their superpowers, claiming to be a superhero himself, but challenges them to a three-on-one battle for proof. Buttercup scoffs at his claim, and they fight to prove what each said was true. Buttercup at first think he is easy to beat, but it turns out that the boy, Dexter, has a metal exo-skeleton in his backpack. After Buttercup's defeat, Blossom and Bubbles join the fight. After Dexter defeats them again, the gym teacher, , arrives and commands them to stop, while Bell and Dr. X watch them from the top of a building.
After Jack had a talk with them he decided to leave them over to Dexter. Bubbles then also met her new friend . Jack explained to her that he got him from a nice old lady who asked if he could take care of him since he was badly wounded, but she never came back to pick him up. Bubbles was along with Courage outside playing when suddenly the appeared from nowhere and attacked her while Courage went to the others to call for help. Blossom, Buttercup and Dexter fight him but he is too strong, eventually Jack comes to save them. After his defeat seems to have been watching the fight. When he wants to leave, he is abducted by Bell and she took him with her to their hideout.
Meanwhile somewhere in , (aka XJ-9) was battling against the but lost when pulled her arm off. Jenny's mother came to her and told to that it was supossed to be a simulation and not a slaughter. Dr. Brisbaine commented that he had a miscalculation. He said to that he was in the "clouds" again and said to to have the report by his desk the next morning. knew that Boomer was thinking about the Powerpuff Girls again and said that he should focus on the operation. Back at the girls were walking through the hallways and two fan-girls named and encountered Buttercup and reacted on her superhero powers. After they were gone Blossom had another encounter with Dexter, and Bubbles also became "friends" with . Meanwhile in the lab of Nora she was trying to fix XJ-9 again with the help of who knew very much about robots and also was very in love with Jenny, to Jenny's dislike. Meanwhile Mojo Jojo was brought to the home of Bell. He encountered the Irken and his puppy disguised dog , who at first seemed to be their leader but turned out to just be a maid. Mojo Jojo then met with Dr. X, and the . Dr. X explained to Mojo that they were planning to take over the Earth but had some obstacles including their most giant threat the Powerpuff Girls. He said that Mojo now is a servant of him and he is trying to seek other people like him and took as an example. Mandark was spying on Dexter and discovered that he had began a relationship with Blossom. Blossom and Dexter were in the library studying. Dexter left and went to inside the school, but was followed by Blossom. When she was inside of the lab she saw a dead girl hanging in the lab and first mistook her for Bubbles...
Upon closer inspection, Blossom saw that the dead girl wasn't Blubble. Dexter came and pushed her out of his lab. Blossom searched for and told him what she saw in Dexter's lab. Otto told her that it was just an but also an except replica of Dexter's older sister . He took Blossom with him through time to let her show Dexter's past. Otto told her that Dee Dee was very annoying and constantly destroyed Dexter's lab. But that was just a normal brother-sister relationship. Dee Dee also took Dexter sometimes with her to talk about nature. Once of those times Dee Dee said to Dexter that if she dies that he shouldn't try to bring her back. Then on another day when Dee Dee sneaked inside of Dexter's lab Mandark broke in along with his . They began to battle until one of the Jackbots fired a laser towards Dexter and Dee Dee tried to save Dexter by jumping in front of it. Mortally wounded by the shot and with the lab destroyed, Dee Dee died from injuries, in Dexter's hands while Mandark fled in grief and terror. This whole scene was watched by Blossom, an experience that would change her forever. There was a funeral for Dee Dee and her and came so as her two best friends and , while Dee Dee was watching when she was being guided away by the . Dexter couldn't accept that his sister was dead and began to make an android of her. But he wanted to make that gynoid as human as possible so he used real human organs in the gynoid. Suddenly Dexter heard voices of Dee Dee about the promise they made. Dexter quickly fled to her grave only to find Mandark, grieving at the tombstone of his lost love, Dee Dee. When he saw him Dexter pulled his scalpel and tried to kill Mandark for what he had done to Dee Dee. When she was back in the normal time she encountered her sister and hugged them, Buttercup reacted angrily and reacted it towards Otto until Blossom told her to stop. Blossom went outside and sat at a tree when she was suddenly attacked by Bell and GIR.
