In the Chatham Islands, 1849, American lawyer Adam Ewing witnesses the whipping of a Moriori slave, Autua. Autua stows away on Ewing’s ship and convinces him to advocate for Autua to join the crew as a free man. Autua saves Ewing’s life before his doctor, Henry Goose, can poison him and steal his gold under the guise of treating him for a parasitic worm. In San Francisco, Ewing and his wife denounce her father’s complicity in slavery and leave to join the abolition movement.
In 1936, English composer Robert Frobisher finds work as an amanuensis to aging composer Vyvyan Ayrs, allowing Frobisher to compose his own masterpiece, “The Cloud Atlas Sextet”; Frobisher reads Ewing’s journal among the books at Ayrs’s mansion. Ayrs demands credit for the sextet and threatens to expose Frobisher’s bisexuality if he refuses. Frobisher shoots Ayrs and goes into hiding, using the name Ewing. He finishes the sextet and shoots himself before his lover Rufus Sixsmith arrives.
In San Francisco, 1973, journalist Luisa Rey meets Sixsmith, now a nuclear physicist. Sixsmith tips off Rey to a conspiracy to create a catastrophe at a nuclear reactor run by Lloyd Hooks, but he is killed by Hooks’s hitman, Bill Smoke, before he can give her a report as proof; Rey finds Frobisher’s letters to Sixsmith and tracks down Frobisher’s sextet. Scientist Isaac Sachs passes her a copy of Sixsmith’s report, but Smoke kills Sachs by blowing up his plane, and runs Rey’s car off a bridge; she escapes, but the report is destroyed. With help from the plant’s head of security, Joe Napier, Rey evades another assassination attempt, which results in Smoke’s death. With a copy of the report from Sixsmith’s niece, she exposes the plot and has Hooks indicted.
In London, 2012, gangster Dermot Hoggins murders a critic after a harsh review of his memoir, generating huge sales. Hoggins’s brothers threaten the publisher, the aging Timothy Cavendish, for Hoggins’s profits. Timothy’s brother, Denholme, tells him to hide at Aurora House. On the way, Timothy reads a manuscript based on Rey’s story. Believing Aurora House is a hotel, Timothy signs papers committing himself and discovers it to be a nursing home where all outside contact is prohibited; Denholme reveals that he sent Timothy there as revenge for an affair with his wife. Timothy escapes with three other residents, resumes his relationship with an old flame, and writes a screenplay about his experience.
In 2144, Sonmi-451 is a “fabricant”, a human cloned for slave labor, kept as a fast food server in a dystopian Neo Seoul. She is exposed to ideas of rebellion by another fabricant, Yoona-939. After Yoona is killed, Sonmi is rescued by rebel Commander Hae-Joo Chang, who exposes Sonmi to the banned writings of Aleksandr Solzhenitsyn and a film version of Cavendish’s experience. Hae-Joo eventually introduces her to the leader of the rebel movement, and shows her that clones are recycled into food for other clones. Sonmi makes a public broadcast of her revelations before the authorities attack, killing Hae-Joo and recapturing Sonmi. After recounting her story to an archivist, she is executed.
In 2321, the tribespeople of the post-apocalyptic Big Island of Hawaii worship Sonmi; their sacred text is taken from her recorded testimony. Zachry Bailey’s village is visited by Meronym, a member of an advanced society called the Prescients who use remnants of high technology, but are dying from a plague. Meronym is searching for a communication station on Mauna Sol to send an SOS to off-world humans. In exchange for healing Zachry’s niece, Catkin, Meronym is guided by Zachry to the station where Sonmi made her recording. Returning home, Zachry finds his tribe slaughtered by the cannibalistic Kona tribe; he kills the sleeping Kona chief and rescues Catkin before he and Meronym save each other from the arriving tribesmen. Zachry and Catkin join Meronym and the Prescients as their ship leaves Big Island. On a distant planet, Zachry is married to Meronym and recounts the story to his grandchildren.