When it's scurvy-prevention day at school, Mindy parades in her float in anticipation for the Little Miss Scurvy beauty pageant, and she insults Mandy, telling her she is ugly. To prove her otherwise, and with Principal Goodvibes' encouragement, Mandy considers entering the pageant. Naturally, Billy and Grim cannot believe Mandy when she tells them about the idea, but finally they decide to help her. Grim calls for Crabina, the Underworld's greatest makeup artist, to give Mandy a complete makeover. Crabina is shocked by Mandy's sour attitude, so she sets up principally to make her smile. At the pageant, Mandy has a real chance at winning the contest, but she still refuses to smile during her heart-warming musical number. Ultimately she smiles, but this event is so powerful that it alters the laws of the universe, and The Grim Adventures universe transforms into the The Powerpuff Girls universe, with Billy, Mandy and Grim turning into the Powerpuff Girls, Irwin turning into Mojo Jojo, and Professor Utonium guest starring as himself in a brief speaking cameo.

When Billy's parents are attacked by an anaconda, Billy suggest visiting boy wizard Nigel Planter, because he can talk to snakes. Planter in fact does not speak to snakes, but to snacks, and instead he asks for Billy, Mandy and Grim's help to win the affections of Huffefnie Pfefferpfeffer, a beautiful witch in the School of Sorcery (and having a striking resemblance to Gladys). Planter tries using a romantic love potion and enchanted chocolates, but they do not work. The guys end up completely forgetting about Billy's parents.

When Billy's parents leave for their second honeymoon, Billy is left alone at the worst possible moment, since he has invited Principal Goodvibes over to dinner so he can recommend him into Rollington Academy for the Gifted. Billy's dad suggest Billy to use Eris, the goddess of chaos, and Hoss Delgado, spectral exterminator, as his substitute parents during the dinner. The dinner is a disaster with Delgado terrorizing Goodvibes, and Eris unleashing giant alien zombie lobsters. Goodvibes forcefully recommends Billy into Rollington Academy, which, as it turns out, is actually a military school.

Then Billy's mom, discovers crow's feet on her face, she panics and does not want to leave the bathroom. As Grim needs to use the bathroom, he uses his scythe to make Gladys a young girl again. Gladys goes to see Billy, but neither he nor Mandy nor Irwin recognize her, and instead, Billy calls her "Corn", because of the white bread she gave him. When Corn tells Billy to do his homework, Mandy tells him to go to the movie theater instead. Corn and Mandy struggle over who gets to control Billy. Billy's father plays with Grim's scythe and also becomes a child; he then goes to the movies and gets together with Gladys (Corn) again.

When Billy, Mandy and Grim notice things have been disappearing in the house, they set out to investigate using a supernatural detector. They find the culprit is a talking "taking tree" in Billy's yard, who has been stealing objects since Billy's dad was a child. To make the tree happy, Mandy and Grim set out to trade the stolen belongings for a highly-valued Mickey Munchle baseball card, which is worth eleventy million dollars. Mandy and Grim return from the baseball shop with the real Mickey Munchle. The tree returns all of the stolen things, but keeps the player.

When the mall's surveillance cameras capture Grim's silhouette attacking endangered owls, a naturalist named Corey Nebraska blames Grim for the attacks, while Mandy suspects Grim is sleepwalking again. Billy, Mandy and Nebraska follow Grim while he sleepwalks, but they realize it is actually Billy's mom, the one attacking the owls. When discovered, Gladys reveals her hatred toward the owls as she recounts the story on how an owl ate her pet rat, Sniffles, years ago. Billy's dad reveals that he was in fact the one who ate Sniffles merely to survive until lunch time.

When Nergal goes to visit Billy's family (his in-laws) for the weekend, he ends up staying with them over a year. When Billy finally asks his uncle to leave, Nergal says he cannot return home because he is a complete failure, having lost at a board game 599 times in a row against his own family, and experiencing constant disappointment elsewhere. Billy and Grim tell him to not worry about being a failure, but to embrace it. After training with Billy and Grim, Nergal returns home and he finally wins at the board game, but he also makes a crack in the ceiling and his home starts filling with lava.

As Billy desires to be "cool" like Sperg, he has an ectoplasmic manifestation coming out of his mouth. The ectoplasm grows full size and turns out to be the ghost of nineteenth-century British poet Lord Byron, who tries to teach Billy to be cool, using elaborate poetry instead of bare muscles. Billy uses a poem to insult Sperg's mother, and Sperg challenges Billy to a duel. Billy and Lord Byron fight Sperg and his gang, but are badly beaten. Byron tells Billy he has been trained in the arts of coolness, and disappears.

As Grim watches the entire season of "My Troubled Pony" (parodying My Little Pony), he learns from Mandy that the show was cancelled and does not have an ending. Grim decides to reap the "Schlubs" (a parody of The Smurfs), 100 creatures that live in Billy's yard, to melt them into gold so he can finance the creation of the series finale. Grim must get past Billy and the aggressive Schlubs themselves, including the single, large female (a parody of Smurfette). After Grim thinks he got the creatures with his scythe, Mandy appears to have used all the gold herself to become rich.

When Billy and Irwin start making prank calls, everybody knows that Billy is behind the calls because every telephone has a caller ID. While Billy searches in Grim's trunk in the basement for something to defeat the caller ID, he finds a skull-shaped phone with no caller ID. Grim warns him to not use the phone, because it is used to call the ancient demon Cthulhu, whose sole appearance makes people go mad, and if awakened will cause the destruction of the world. Despite Grim's warning, Billy and Irwin use the phone anyway, and they are sucked into it by tentacles.

The day before Christmas, Billy, Mandy and Grim go to the shopping mall, where Mandy complains that Santa Claus is just an invention from corporations. Grim assures Mandy that Santa is real, and they even went to college together. They decide to travel to the North Pole and meet Santa, but when they arrive Mrs. Claus tells them that Santa Claus has been transformed into a vicious vampire.