Mojo Jojo steals a magical Anubis dog head and unleashes a curse that turns everyone into dogs, including the Powerpuff Girls, but the three sniff out a solution and show Mojo Jojo that their bite is worse than his bark.
The girls find something uneasy about the Professor's new girlfriend Ima Goodlady. It turns out that she's really the sinister Sedusa, who gets the girls grounded so she can commit crimes around Townsville, such as making off with the Mayor's jewels.
Vile villain Roach Coach plots to infest Townsville with his army of cockroaches. The girls must fight their fear of bugs in order to squash Roach Coach's scheme and force him to bug off.
Three escaped convicts, repeatedly beaten by the girls, fashion themselves new identities when they find grown-up-sized Powerpuff Girls costumes inside Townsville Jail. Using their pseudo-superhero status, they glamour civilians of money and jewellery while the Mayor mistakenly calls the police and has the real Powerpuff Girls thrown into prison.
The heinous HIM toys with Bubbles' mind by speaking to her through Octi, her favorite stuffed animal. Following its instruction, Bubbles provokes a fight between her sisters that prompts the Professor to issue a time-out until the girls can make amends and make squid-meat out of the now giant, HIM-controlled Octi.
The Amoeba Boys' ill-conceived plan to stand in front of the "Keep off the Grass" sign at Townsville park all night in the rain leaves them with a terrible virus. When they infect the Townsville population, it's up to the girls to find the antidote.
Buttercup develops a crush on Ace, the leader of the Ganggreen Gang. However, when the gang exploits her infatuation and lures Blossom and Bubbles into danger, Buttercup quickly comes to her sisters' rescue and shows the boys the real meaning of the word "crush."
The beastly bumpkin Fuzzy Lumpkins goes wild in Townsville and only the Powerpuff Girls, with some help from a flying squirrel, can teach him to respect other people's property.