The story jumps between eras until each storyline eventually resolves, spanning hundreds of years. Writings from characters in prior storylines are found in future storylines. Characters appear to recur in each era, but change relationships to each other. Slaves or abusers often change roles, suggesting reincarnation or other connection between souls through the ages.
In the Chatham Islands, 1849, American lawyer Adam Ewing witnesses the whipping of Autua, an enslaved Moriori man. Autua stows away on Ewing’s ship and persuades 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 from 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 and wounds Ayrs and goes into hiding. 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, who secretly promotes oil-energy interests. 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, just as Frobisher had found Ewing’s journal earlier. She tracks down Frobisher’s obscure sextet in a record store. Scientist Isaac Sachs passes her a copy of Sixsmith’s report. Smoke kills Sachs by blowing up his plane and then runs Rey’s car off a bridge, destroying the report. With help from the plant’s head of security, Joe Napier, Rey evades another assassination attempt, and Smoke is killed. 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.