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- George Beard - the 9 3/4-year-old boy with a flat head. He wears a neck tie.
- Harold Hutchins - a next-door-neighbor of George.
- Mr. Benny Krupp - Mr. Krupp is the school principal of George and Harold
- Captain Underpants - the alter-ego of Principal Krupp
- Ms. Ribble - the fourth grade teacher of George and Harold
- Melvin Sneedly - George and Harold's nemesis. he wears glasses and a bow tie
- Heidi Hutchins - Harold's sister
- Henry Hutchins - Harold's grandfather
- Jane - Henry Hutchins' girlfriend and George Beard's great-grandmother
- Ingrid Ashley and Larry Zarrow - The local TV reporters for Eyewitness News (Channel 4).
- Dr. Diaper - an evil scientist who wears a diaper
- The Talking Toilets- Toilets that shout "YUM, YUM, EAT 'EM UP!"and eat people, created when George and Harold wrote it in a comic book, and fed it to an animating machine created by Melvin Sneedley
- The Turbo-Toilet 200- The master of the talking toilets.
- Jennifer - an evil alien from Mercury
- Zorx and Klax - Jennifer's innocent cousins. They tried helped him take over Earth.
- Professor Poopypants- a scientist from New Swissland that forced everyone to change their name to what the Name Change-o-Cart 300 says. Later changed his name to Tippy T. Tinkletrousers.
- Wedgie Woman - Ms. Ribble after hypnosis from George and Harold
- Evil George and Evil Harold - George and Harold's evil twin from the alternate dimension, first met when a horrible accident with the time machine occurred
- Captain Blunderpants - Captain Underpants' evil twin from the alternate dimension