| Tom Hanks | | Dr. Henry Goose / Hotel Manager / Isaac Sachs / Dermot Hoggins / Cavendish Look-a-Like Actor / Zachry |
| Halle Berry | | Native Woman / Jocasta Ayrs / Luisa Rey / Indian Party Guest / Ovid / Meronym |
| Jim Broadbent | | Captain Molyneux / Vyvyan Ayrs / Timothy Cavendish / Korean Musician / Prescient 2 |
| Hugo Weaving | | Haskell Moore / Tadeusz Kesselring / Bill Smoke / Nurse Noakes / Boardman Mephi / Old Georgie |
| Jim Sturgess | | Adam Ewing / Poor Hotel Guest / Megan's Dad / Highlander / Hae-Joo Chang / Adam (Zachry's Brother-in-Law) |
| Bae Doona | | Tilda / Megan's Mom / Mexican Woman / Sonmi-451 / Sonmi-351 / Sonmi Prostitute |
| Ben Whishaw | | Cabin Boy / Robert Frobisher / Store Clerk / Georgette / Tribesman |
| Keith David | | Kupaka / Joe Napier / An-kor Apis / Prescient |
| James D'Arcy | | Young Rufus Sixsmith / Old Rufus Sixsmith / Nurse James / Archivist |
| Xun Zhou | | Talbot (Hotel Manager) / Yoona-939 / Rose |
| David Gyasi | | Autua / Lester Rey / Duophysite |
| Susan Sarandon | | Madame Horrox / Older Ursula / Yusouf Suleiman / Abbess |
| Hugh Grant | | Rev. Giles Horrox / Hotel Heavy / Lloyd Hooks / Denholme Cavendish / Seer Rhee / Kona Chief |
| Robert Fyfe | | Old Salty Dog / Mr. Meeks / Prescient 1 |
| Martin Wuttke | | Mr. Boerhaave / Guard / Leary the Healer |
| Robin Morrissey | | Young Cavendish |
| Brody Nicholas Lee | | Javier Gomez / Jonas / Zachry's Older Nephew |
| Ian van Temperley | | Enforcer |
| Amanda Walker | | Veronica |
| Ralph Riach | | Ernie |
| Andrew Havill | | Mr. Hotchkiss |
| Tanja de Wendt | | Mrs. Hotchkiss |
| Raevan Lee Hanan | | Little Girl with Orison at Papa Song's / Catkin / Zachry Relative 1 |
| Götz Otto | | Groundsman Withers |
| Niall Greig Fulton | | Haskell Moore's Dinner Guest 2 / Mozza Hoggins |
| Louis Dempsey | | Haskell Moore's Dinner Guest 3 / Jarvis Hoggins |
| Martin Docherty | | Haskell Moore's Dinner Guest 4 / Eddie Hoggins |
| Alistair Petrie | | Haskell Moore's Dinner Guest 1 / Musician / Felix Finch / Lascivious Businessman |
| Zhu Zhu | | Megan Sixsmith / 12th Star Clone |
| Sylvestra Le Touzel | | Haskell Moore's Dinner Guest 5 / Nurse Judd / Aide in Slaughtership |
| Jojo Schöning | | Papa Song Punk |
| Laura Vietzen | | Young Ursula |
| Thomas Kügel | | Ursula's Father |
| Marie Rönnebeck | | Ursula's Daughter |
| Ruby Kastner | | Young Girl |
| Emma Werz | | Ursula's Granddaughter |
| Mya-Lecia Naylor | | Miro |
| Korbyn Hawk Hanan | | Adam Grandson |
| Katy Karrenbauer | | Axwoman |
| Dulcie Smart | | Ursula's Mother / Herbalist |