Nat Faxon as Captain Underpants / Mr. Krupp (voice)

Jay Gragnani as Harold (voice)

Ramone Hamilton as George (voice)

Sean Astin as Narrator / Mr Gigglenose (voice)

Dayci Brookshire as Jessica / Dressy (voice)

Clancy Brown as Mr. Ree (voice)

Jorge Diaz as Melvin / Stanley Peet / Melvin's Dad (voice)

Peter Hastings as Comic Narrator (voice)

Evan Kishiyama as Steve "Gooch" Yamaguchi (voice)

David Koechner as Mr. Meaner (voice)

Erica Luttrell as Erica / George's Mom (voice)

Patty Mattson as Miss Anthrope / Harold's Mom (voice)

Brennan Murray as Bo Hweemuth (voice)

Kevin Michael Richardson as Diddlysaurus / George's Dad (voice)

Mindy Sterling as Melvin's Mom (voice)

Stephen Tobolowsky as Creepy Rattlechains (voice)

Kari Wahlgren as Mayor Hoppy McChapper (voice)