- Nicolas Cage as Benjamin Franklin Gates, a cryptologist and treasure hunter.
- Diane Kruger as Abigail Chase, a historian and linguist who is Gates' love interest.
- Justin Bartha as Riley Poole, Gates' tech-savvy friend and partner.
- Jon Voight as Patrick Gates, Benjamin's father and a former treasure hunter.
- Harvey Keitel as Agent Peter Sadusky, an FBI agent who is initially suspicious of Gates but later becomes his ally.
- Sean Bean as Ian Howe, a ruthless treasure hunter who is Gates' main rival.
- Helen Mirren as Dr. Emily Appleton, a historian and mentor to Gates.