| Reese Witherspoon | | Susan Murphy / Ginormica (voice) |
| Seth Rogen | | B.O.B. (voice) |
| Hugh Laurie | | Dr. Cockroach Ph.D. (voice) |
| Will Arnett | | The Missing Link (voice) |
| Kiefer Sutherland | | General W.R. Monger (voice) |
| Rainn Wilson | | Gallaxhar (voice) |
| Stephen Colbert | | President Hathaway (voice) |
| Paul Rudd | | Derek Dietl (voice) |
| Julie White | | Wendy Murphy (voice) |
| Jeffrey Tambor | | Carl Murphy (voice) |
| Amy Poehler | | Computer (voice) |
| Ed Helms | | News Reporter (voice) |
| Renée Zellweger | | Katie (voice) |
| John Krasinski | | Cuthbert (voice) |
| Sean Bishop | | Private Bullhorn / Helicopter Pilot / Advisor Ortega (voice) |
| Rich Dietl | | Commander / Advisor Smith (voice) |
| Stephen Kearin | | Technician Ben (voice) |
| Rob Letterman | | Secret Service Man #1 / Lieutenant (voice) |
| Tom McGrath | | Wilson (voice) |
| Chris Miller | | Advisor Cole / Army Commander Jones (voice) |
| Mike Mitchell | | Advisor Wedgie (voice) |
| Kent Osborne | | Technician Jerry (voice) |
| Latifa Ouaou | | Advisor Ouaou / Mrs. Ronson / Female Advisor #2 / Panicked Guest (voice) |
| Geoffrey Pomeroy | | Soldier #4 / Pilot / Soldier #3 / News Technician (voice) |
| David P. Smith | | Soldier #1 / Advisor Jackson (voice) |
| Lisa Stewart | | Bridesmaid Candy (voice) |
| Conrad Vernon | | Advisor Hawk / Advisor Dither / Minister / Secret Service Man #2 / Mama Dietl (voice) |