- Reese Witherspoon as Susan Murphy / Ginormica
- Paul Rudd as Derek
- Hugh Laurie as Dr. Cockroach, Ph.D.
- Will Arnett as The Missing Link
- Seth Rogen as B.O.B.
- Kiefer Sutherland as Gen. W.R. Monger
- Stephen Colbert as The President of the United States
- Rainn Wilson as Gallaxhar
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