Reese Witherspoon as Susan Murphy / Ginormica (voice)

Seth Rogen as B.O.B. (voice)

Hugh Laurie as Dr. Cockroach Ph.D. (voice)

Rainn Wilson as Gallaxhar (voice)

Will Arnett as The Missing Link (voice)

Kiefer Sutherland as General W.R. Monger (voice)

Paul Rudd as Derek Dietl (voice)

Stephen Colbert as President Hathaway (voice)

Julie White as Wendy Murphy (voice)

Jeffrey Tambor as Carl Murphy (voice)

Amy Poehler as Computer (voice)

Ed Helms as News Reporter (voice)

Renée Zellweger as Katie (voice)

Sean Bishop as Private Bullhorn / Helicopter Pilot / Advisor Ortega (voice)

Rich Dietl as Commander / Advisor Smith (voice)

Rob Letterman as Secret Service Man #1 / Lieutenant (voice)

Tom McGrath as Wilson (voice)

Chris Miller as Advisor Cole / Army Commander Jones (voice)

Mike Mitchell as Advisor Wedgie (voice)

Kent Osborne as Technician Jerry (voice)

Latifa Ouaou as Advisor Ouaou / Mrs. Ronson / Female Advisor #2 / Panicked Guest (voice)

Geoffrey Pomeroy as Soldier #4 / Pilot / Soldier #3 / News Technician (voice)

David P. Smith as Soldier #1 / Advisor Jackson (voice)

Lisa Stewart as Bridesmaid Candy (voice)

Conrad Vernon as Advisor Hawk / Advisor Dither / Minister / Secret Service Man #2 / Mama Dietl (voice)

John Krasinski as Cuthbert (voice)

Stephen Kearin as Technician Bee (voice)