The protagonist of each story is indicated in bold.
| Actor | Pacific Islands, 1849 | Cambridge / Edinburgh, 1936 | San Francisco, 1973 | London, 2012 | Neo Seoul, 2144 | Big Island, 106 winters after The Fall (2321) |
|---|---|---|---|---|---|---|
| Tom Hanks | Dr. Henry Goose | Hotel Manager | Isaac Sachs | Dermot Hoggins | Cavendish Look-alike Actor | Zachry Bailey |
| Halle Berry | Native Woman | Jocasta Ayrs | Luisa Rey | Indian Party Guest | Ovid | Meronym |
| Jim Broadbent | Captain Molyneux | Vyvyan Ayrs | — | Timothy Cavendish | Korean Musician | Prescient |
| Jim Sturgess | Adam Ewing | Poor Hotel Guest | Megan's Dad | Highlander | Hae-Joo Chang | Adam (Zachry's Brother-in-Law) |
| Ben Whishaw | Cabin Boy | Robert Frobisher | Record Store Clerk | Georgette Cavendish | — | Tribesman |
| Doona Bae | Tilda Ewing | — | Megan's Mom, Mexican Woman | — | Sonmi-451, Sonmi-351, Sonmi Prostitute | — |
| Hugo Weaving | Haskell Moore | Tadeusz Kesselring | Bill Smoke | Nurse Noakes | Boardman Mephi | Old Georgie |
| Hugh Grant | Rev. Giles Horrox | Hotel Heavy | Lloyd Hooks | Denholme Cavendish | Seer Rhee | Kona Chief |
| Susan Sarandon | Madame Horrox | — | — | Older Ursula | Yosouf Suleiman | Abbess |
| Keith David | Kupaka | — | Joe Napier | — | An-kor Apis | Prescient |
| James D'Arcy | — | Young Rufus Sixsmith | Old Rufus Sixsmith | Nurse James | Archivist Park | — |
| Zhou Xun | — | — | Talbot (Hotel Manager) | — | Yoona-939 | Rose |
| David Gyasi | Autua | — | Lester Rey | — | — | Duophysite |
| Robert Fyfe | Old Salty Dog | — | — | Mr. Meeks | — | Prescient |
Other cast members who appear in more than one segment include Martin Wuttke, Brody Nicholas Lee, Alistair Petrie, and Sylvestra Le Touzel.[15] In addition, author David Mitchell makes a cameo appearance as a double agent in the futuristic Korea section.[16]
