Each issue of The Powerpuff Girls: Super Smash-Up! features the main characters (Blossom, Bubbles, and Buttercup) teaming up with other characters from Cartoon Network such as Dexter's Laboratory, Courage the Cowardly Dog, Johnny Bravo and more.
- Issue One: Just when you thought you'd seen it all, Cartoon Network Crossover Craziness continues! After their victory in the Super Secret Crisis War!, the Powerpuff Girls take it easy with a rare VIP tour of Dexter's Laboratory! But when tag-along Dee Dee accidentally activates Dexter's newest invention, the fate of the entire multiverse is suddenly at stake! Plus: a bonus Courage the Cowardly Dog story by the Glyph- and Eisner-nominated Princeless's Jeremy Whitley!
- Issue Two: The Powerpuff Girls’ inter-dimesional search for Dexter’s mutated sister Dee Dee has brought them to the Bagge Farmhouse in the middle of Nowhere! But when they are mistaken for dog sitters, the Girls find themselves thrust into the disturbing nightmare that is Courage’s life. Plus, a Foster’s Home for Imaginary Friends story—Bloo starts a “Small Club” while Wilt starts a “Tall Club” in response…
- Issue Three: The Powerpuff Girls follow the monstrously mutated Dee Dee's trail to the world of Cow and Chicken! Too bad Red Guy has gotten to her first! His plan? Make Dee Dee a superstar! Can Cow, Chicken and the Powerpuff Girls reach Dee Dee before she signs her life away?? Plus, a short story featuring The Grim Adventures of Billy and Mandy...and a beauty pageant? That's not gonna be pretty...
- Issue Four: The Girls have tracked the mutated Dee Dee to Foster's Home For Imaginary Friends! Too bad it's right in the middle of Ultimate Hide n Seek!. Plus, a bonus Mojo Jojo story by Ivan Cohen with art by Nneka Myers! In "No Money, Mojo Problems", Mojo seeks... alternative funding... for his evil deeds.
- Issue Five: The Powerpuff Girls enlist Mojo Jojo to help them catch Dee Dee in Camp Kidney before the entire multiverse falls apart! What could possibly go wrong? Plus, a puuurrrr-fect bonus Dexter's Laboratory story, Dexter accidentally turns himself into a cat and must try and get Dee Dee to turn him back without being able to communicate.
The Powerpuff Girls
- Professor Utonium
- The Mayor
- Ms. Bellum
- Talking Dog
- Mojo Jojo
- Fuzzy Lumpkins
- Princess Morbucks
- Gangreen Gang
- Steve the Monster
Courage the Cowardly Dog
- The Spirit Of The Harvest Moon
Foster's Home for Imaginary Friends
- Mr. Herriman
- Fluffer Nutter
- Jackie Khones
- Bloppy Pants
- Burple Bear
- New Guy
- Keystone Blop
- Uncle Pockets
Cow and Chicken / I Am Weasel
- Cow / Supercow
- Red Guy
- I.M. Weasel
- I.R. Baboon
The Grim Adventures of Billy & Mandy
- Scoutmaster Lumpus
Ed, Edd n Eddy
- Johnny Bravo
Codename: Kids Next Door
- Numbuh 1
Ben 10: Omniverse
- Ben Tennyson
- Despite being a crossover comic, is actually part of the franchise of The Powerpuff Girls.
- The comic is inspired by the DC Comics Television series Batman: The Brave and the Bold.
- The Mayor and Mojo Jojo made a cameo in the issue 1 of the main "Powerpuff Girls: Super Smash-Up!" chapter.
- In "Issue Four"s Main Story:
- It is the second time that Steve having an "Annual Monster Day", the first was in "Monster Mash", IDW's The Powerpuff Girls Issue Seven & Issue Eight.
- Him's lime eyes is slightly different to have the white eyes, as opposed to the usual lime green eyes.
- It is the second time that The Justice Friends arrived to Townsville in the series, the first was in "Members Only".
- Major Glory said "Justice Friends Assemble!" when they are ready to fight Him, Princess Morbucks and Steve in Townsville, was a parody of Marvel's Avengers where they said "Avengers Assemble!".
- In "Issue Four"'s Bonus Story:
- This is the first time Mojo Jojo gets a job.
- This is also the first time Mojo Jojo fights Him.
- In "Issue Five"'s Main Story:
- Mojo Jojo is set plan turn the multiverse to Mojoverse.