| Chara | Voice Actor | Bio | Episodes |
| Mojo Jojo | Roger Jackson | Superintelligent ape | Monkey See, Doggie Do / Telephonies / Mr. Mojo's Rising / Bubblevicious / The Bare Facts / Just Another Manic Mojo / The RowdyRuff Boys / Uh Oh Dynamo / Supper Villain |
| Ima Goodelady | Jennifer Hale | Disguise used by Seduca | Mommy Fearest |
| Seduca | Jennifer Hale | Female villain with deadly hair | Mommy Fearest |
| Roach Coach | Roger Jackson | King of all roaches | Insect Inside |
| Cadet Skippy | none | Scout for the roach army | Insect Inside |
| Criminal 017 | Kevin M. Richardson (?) | Dresses as Bubbles | PowerPuff Bluff |
| Criminal 253 | Jeff Glen Bennett (?) | Dresses as Blossom | PowerPuff Bluff |
| Criminal 002 | Jeff Glen Bennett (?) | Dresses as Buttercup | PowerPuff Bluff |
| Him | Tom Kane | The evilest of evil and cruelest of cruel | Octi Evil / Telephonies / Tough Love |
| the Amoeba Boys | Chuck McCann | Gang of one cell criminals | Geshundfight |
| Ace | Jeff Glenn Bennett | Leader of the Gangrene Gang | Buttercrush / Telephonies / School House Rocked |
| Snake | Tom Kenny | Member of the Gangrene Gang | Buttercrush / Telephonies / School House Rocked |
| Little Arturo | Carlos Alazraqui / Tom Kenny | Member of the Gangrene Gang | Buttercrush / Telephonies / School House Rocked |
| Big Billy | Jeff Glenn Bennett | Member of the Gangrene Gang | Buttercrush / Telephonies / School House Rocked |
| Grubber | Jeff Glenn Bennett | Member of the Gangrene Gang | Buttercrush / Telephonies / School House Rocked |
| Fuzzy Lumkins | Jim J. Cummings | Angry furball from the country | Fuzzy Logic / Telephonies / Impeach Fuzz |
| the Boogie Man | Kevin M. Richardson | Leader of an army of evil | Boogie Frights |
| Scissors | Jeff Glenn Bennett | A monster | Boogie Frights |
| Al Lussion | Frank Wilker | A magician killed during a performance | Abracadaver |
| Abracadaver | Frank Wilker | A magical zombie | Abracadaver |
| Major Man | Jeff Glenn Bennett | A superhero who causes crimes | Major Competition |
| Elmer Slue | Dee Bradley Baker | A student at Pokey Oaks Kindergarten who became a glue creature | Paste Makes Waste |
| the Cat | Mark Hamill | An evil cat bent on taking over the world | Cat Man Do |
| Rainbow the Clown | Tom Kenny | A clown who has a run in with a bleach truck | Mime for a Change |
| Mr. Mime | Tom Kenny | Just your average evil mime | Mime for a Change |
| Brick | Rob Paulsen | Leader of the RowdyRuff Boys (Blossom's opposite) | The RowdyRuff Boys |
| Boomer | Rob Paulsen | Member of the RowdyRuff Boys (Bubbles's opposite) | The RowdyRuff Boys |
| Butch | Roger L. Jackson | Member of the RowdyRuff Boys (Buttercup's opposite) | The RowdyRuff Boys |
| the Fish Balloon | Kevin M. Richards | A monster native to the Bonzai Gardens Park | Uh Oh Dynamo |
| Princess | Jennifer Hale | A spoiled brat needing a swift kick in the pants | Stuck Up, Up and Away |
| Lenny Baxter | Tom Kenny | The resident comicbook geek | Collect Her |
| Harold Smith | Jeff Glenn Bennett | The average guy living next door to the PowerPuff Girls... who just happens to snap | Supper Villain |
