Chris Rock as Osmosis Jones (voice)

Laurence Fishburne as Thrax (voice)

David Hyde Pierce as Drix (voice)

Brandy Norwood as Leah (voice)

Bill Murray as Frank Detorre

Molly Shannon as Mrs. Boyd

William Shatner as Mayor Phlegmming (voice)

Ron Howard as Tom Colonic (voice)

Sherry Lynn as (voice)

Mickie McGowan as Additional Character Voice (voice)

Chris Elliott as Bob

Elena Franklin as Shane Detorre

Kid Rock as Kidney Rock

Uncle Kracker as Kidney Rock (voice)

Carlos Alazraqui as Additional Character Voices (voice)

Rodger Bumpass as Additional Character Voices (voice)

Richard Steven Horvitz as Additional Character Voices (voice)

Danny Mann as Additional Character Voices (voice)

Mickie McGowan as Additional Character Voices (voice)

Jonathan Adams as Additional Character Voices (voice)