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 Dr. Henry Goose, hoping to steal Ewing's gold, can deliver poison he claims will treat 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 Cloud Atlas 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 Cloud Atlas 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 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 "Cloud Atlas Sextet." Scientist Isaac Sachs passes her a copy of Sixsmith's report. 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 oil executives are indicted.
In London, 2012, Dermot Hoggins, author of a gangster memoir, murders a critic after a harsh review, generating huge sales. Hoggins's brothers threaten the publisher, the aging Timothy Cavendish, for Hoggins's profits. Cavendish's brother Denholme tells him to hide at Aurora House. On the way, Cavendish reads a manuscript based on Luisa's story. Believing Aurora House is a hotel, Timothy signs papers committing himself; in fact, Aurora House is a nursing home. Denholme reveals to Timothy that he sent him there as revenge for Timothy's affair with Denholme's wife. The head nurse, Noakes, is abusive, and denies contact with the outside world. Cavendish escapes with three other residents, resumes his relationship with an old flame, and writes a screenplay about his experience.
In Seoul, 2144, Sonmi-451 is a "fabricant," a human cloned for slave labor, kept as a fast food server in a dystopian Neo Seoul, Korea. 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. He exposes Sonmi to the banned writings of Aleksandr Solzhenitsyn and a film version of Cavendish's experience. After Sonmi is captured, Hae-Joo rescues her, 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 manifesto. The authorities attack; Hae-Joo is killed and Sonmi is recaptured. After recounting her story to an archivist, she is executed.
In 2321, the tribespeople of the post-apocalyptic Big Island of Hawaii worship Sonmi-451; their sacred text is taken from her broadcast. Zachry Bailey is plagued by visions of a demonic figure, Old Georgie. Zachry, his brother-in-law Adam, and his nephew are attacked by the cannibalistic Kona tribe. Zachry runs into hiding and his companions are murdered. His village is visited by Meronym, a member of the Prescients, an advanced society using remnants of high technology, but who 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, Zachry guides Meronym to the station where Sonmi-451 made her broadcast. Returning, Zachry finds his tribe slaughtered by the Kona. He kills the sleeping Kona chief and rescues Catkin, and Meronym uses her gun to save him from the Kona and is saved by Zachry. Zachry and Catkin join Meronym and the Prescients as their ship leaves Big Island. On a distant planet, Zachry recounts the story to his grandchildren and joins Meronym.