Each issue of The Powerpuff Girls: Super Smash-Up! features the main characters (Blossom, Bubbles, and Buttercup) teaming up with other characters from the 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, Cow and Chicken 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
- Dee Dee
- The Justice Friends
- Major Glory
- Miss Spell
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
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.
- Supercow, Chicken (got tied up) and Red Guy were made a cameo in the issue 1 of the main "Powerpuff Girls: Super Smash-Up!" chapter.
- Cow's Database (which appear in the issue 3 last pages of the main "Powerpuff Girls: Super Smash-Up!" chapter) made a cameo in the issue 5.
- In "Issue Three"'s Main Story:
- The drawing style comic is quite different to "Super Secret Crisis War!".
- This is the third time I.M. Weasel makes two cameos appears episode Chickens Don't Fly and Magic Chicken.
- The Intruder Helmet that Red Guy Controls Weasel is similar to "The Mind Controlling Helmet" from Nickelodeon's 2004 movie "The SpongeBob SquarePants Movie".
- Red Guy's nickname is revealed to be "Hiney Guy".
- This is very first time the Red Guy is the Max Schreck's Impersonation.
- Mom and Dad are redesign in one comic.