The book consists of six nested stories, from the remote South Pacific in the nineteenth century to a distant, post-apocalyptic future. Each tale is read (or observed) by the main character in the next. The first five stories are each interrupted at a pivotal moment. After the sixth story, the other five stories are closed, in reverse chronological order, and each ends with the main character reading or observing the chronologically previous work in the chain. Each story contains a document, movie, or tradition that appears in a previous story.
The Pacific Journal of Adam Ewing (Part 1)
The first story begins in the Chatham Islands (one of the islands of New Zealand), in 1850, where Adam Ewing, a guileless American notary from San Francisco during the California Gold Rush, awaits repairs to his ship. Ewing witnesses a Moriori slave being flogged by a Maori overseer. During the punishment, the victim, Autua, sees pity in the eyes of Adam Ewing and smiles. Later Ewing ascends a high hill called Conical Tor, and stumbles into its crater, where he finds himself surrounded by faces carved into trees. Reasoning that those who carved the faces must have had egress from the crater, he escapes. As the ship gets underway, Dr. Goose, Ewing's only friend aboard the ship, examines the injuries sustained on the volcano and Ewing also mentions his chronic ailment. The doctor diagnoses it as a fatal parasite, and recommends a course of treatment. Meanwhile, Autua has stowed away in Ewing's cabin; and Ewing breaks this news to the Captain, to whom Autua proves himself a first class seaman, whereupon the Captain puts him to work for his passage to Hawaii.
Letters from Zedelghem (Part 1)
The next story is set in Zedelghem, near Bruges, Belgium, in 1931. It is told in the form of letters from Robert Frobisher, a recently disowned and penniless, bisexual young English musician, to his lover Rufus Sixsmith, after Frobisher journeys to Zedelghem as an amanuensis to the reclusive composer Vyvyan Ayrs, who is dying of syphilis and nearly blind. Soon, Frobisher and Ayrs produce Der Todtenvogel ("The Death Bird"), performed nightly in Kraków, and Frobisher has begun composing his own music again. Frobisher and Ayrs' wife Jocasta become lovers, but her daughter Eva remains suspicious of him. Frobisher sells rare books from Ayrs' collection to a fence, including half of The Pacific Journal of Adam Ewing, and reveals that Dr. Goose is poisoning Adam. Once, Ayrs has Frobisher write a song inspired by a dream of a "nightmarish cafe", deep underground, wherein "the waitresses all had the same face", and ate soap. As the summer comes to an end, Jocasta thanks Frobisher for "giving Vyvyan his music back", and Frobisher agrees to stay until next summer.
Half-Lives: The First Luisa Rey Mystery (Part 1)
The third story is written in the style of a mystery/thriller novel, set in the fictional city of Buenas Yerbas, California, in 1975, where Luisa Rey, a young journalist, investigates reports that a new nuclear power plant is unsafe. Rufus Sixsmith meets Luisa in a defective elevator and listens to her life story, wherein her late father was one of the few incorruptible policemen in the city. After the elevator's motive power is restored, Sixsmith expresses to Luisa his concern that the Seaboard HYDRA nuclear power plant is not safe. He is murdered shortly after this admission, and Luisa learns that the businessmen in charge of the plant are assassinating potential whistle-blowers. From Sixsmith's hotel room, Luisa acquires some of Frobisher's letters. Before Luisa can report her findings on the nuclear power plant or Sixsmith's murder, a Seaboard-hired assassin who has been following her forces her — along with Sixsmith's incriminating report — off a bridge.
The Ghastly Ordeal of Timothy Cavendish (Part 1)
The fourth story is comic in tone, and is set in Britain in the present day, wherein Timothy Cavendish, a 65-year-old vanity press publisher, flees the brothers of his gangster client. Cavendish's brother, exasperated by Timothy's endless pleas for financial aid, books him into a nursing home from which Timothy cannot escape. He attempts flight, but is stopped by a security guard. Timothy briefly mentions reading a manuscript entitled Half-Lives: The First Luisa Rey Mystery, but is not impressed by the prospective author's manuscript. Timothy settles into his new surroundings, while still trying to plot a way out. One day, he is struck by a seizure, just as the chapter ends.
An Orison of Sonmi~451 (Part 1)
The fifth story is set in Nea So Copros, a dystopian futuristic state in Korea, derived from corporate culture. It is told in the form of an interview between Sonmi~451 and an "archivist" recording her story. Sonmi~451 is a genetically engineered fabricant (clone): one of many grown to work, among other places, at a fast-food restaurant called Papa Song's. Fabricants are slaves used by "pureblood" society, who retard the fabricants' consciousness by chemical manipulation. In her own narration, Sonmi encounters members of a rebellion, disguised as students, who assist her to become self-aware, or "ascended"; and describes watching The Ghastly Ordeal of Timothy Cavendish as a pre-Skirmishes film (wherein the "Skirmishes" are a major global disaster or war that destroyed most of the world except Nea So Copros (East Asia), and foreshadows "The Fall" in the subsequent chapter "Sloosha's Crossin," in which Nea So Copros, and most of humanity's technological ability, have ended in a second major disaster; the destroyed areas are identified as "deadlands," which are full of disease, ruins, and radioactive contamination). When Cavendish suffers his seizure, a student tells Sonmi and her rescuer Hae-Joo Im that Professor Mephi, Hae-Joo's professor and handler, has been arrested, and that policy enforcers have orders to interrogate Hae-Joo and kill Sonmi on sight. Hae-Joo then identifies himself as a rebel to Sonmi.
Sloosha's Crossin' an' Ev'rythin' After
The sixth story occupies the central position in the novel and is the only one not interrupted, wherein Zachry, an old man, tells a story from his youth. It is gradually revealed that he lives in a post-apocalyptic society on the Big Island of Hawaii. His people, the valley folk, are peaceful farmers, but are often raided by the Kona tribe. Zachry's people worship a goddess called Sonmi, and recall a 'Fall' in which the civilized peoples of Earth — known as the 'Old Uns' — collapsed, and left the survivors to primitivism. Big Island is occasionally visited and studied by a technologically sophisticated people known as the Prescients, whereof a woman called Meronym comes to stay with the villagers. Zachry becomes suspicious of her, and sneaks into her room, where he finds an 'orison,' an egg-shaped device for recording and holographic videoconferencing. Later, Zachry's sister Catkin is poisoned by a scorpion fish, and Meronym reluctantly gives her medicine. When Meronym later requests a guide to the top of Mauna Kea volcano, Zachry reluctantly guides her, there to the ruins of the Mauna Kea Observatories. Here, Meronym shocks Zachry by telling him that their god Sonmi was a human being, and explains the orison. Upon their return, they go with most of the valley-folk to trade at Honokaa; but Zachry's people are imprisoned by the Kona. Zachry and Meronym eventually escape, and she takes him to a safer island. The story ends with Zachry's child recalling that his father told many unbelievable tales; whereas this one may be true, because he has inherited Zachry's copy of Sonmi's orison, which he often watches, even though he does not understand her language.
An Orison of Sonmi~451 (Part 2)
Guided by Hae-Joo Im, Sonmi learns that the fabricants are not released after serving their time at work, but recycled into food and more fabricants. At the rebels' encouragement, she writes a series of abolitionist Declarations and calls for rebellion. She is then arrested, and finds herself telling her tale to the archivist, to whom she reveals that everything that happened to her, including the rebellion, was instigated by the government to encourage the oppression of fabricants by purebloods; but her Declarations will be inspirational nonetheless. Her last wish before her death is to finish watching Cavendish's story, which she is presumed to do.
The Ghastly Ordeal of Timothy Cavendish (Part 2)
Having mostly recovered from his stroke, Cavendish meets a small group of residents also anxious to escape the nursing home: Ernie, Veronica, and the extremely senile Mr. Meeks. He assists their conspiracy to trick Johns Hotchkiss, a fellow-patient's grown son, into leaving his car vulnerable to theft. They seize the car and escape, stopping at a bar to celebrate their freedom. Due to a map Cavendish accidentally left back in his room, however, they are nearly recaptured by Hotchkiss and the staff, but are rescued when Mr. Meeks abruptly exhorts the local drinkers to come to their aid.
It is thereafter revealed that Cavendish's secretary Mrs. Latham recorded the men he was originally fleeing vandalising his office on video, and blackmailed the vandals therewith, allowing him to return to his former life in safety. Subsequently, Cavendish obtains the second half of Luisa Rey's story.
Half-Lives: The First Luisa Rey Mystery (Part 2)
Rey escapes from the sinking car, but is still pursued by Smoke, the assassin working for Seaboard. She picks up her copy of Robert Frobisher's obscure Cloud Atlas Sextet and is astonished to find that she recognizes it, even though it is a very rare piece. Smoke lures her with a copy of Rufus Sixsmith's report about the power plant; but Joe Napier comes to her rescue, and Smoke and Napier kill each other. Later, Rey exposes the corrupt corporate leaders to the public. At the end of the story, she receives a package from Sixsmith's niece, which contains eight more letters from Robert Frobisher to Sixsmith.
Letters from Zedelghem (Part 2)
Frobisher continues to pursue his work with Ayrs while developing his own Cloud Atlas Sextet; becomes besotted with Ayrs's daughter after she subtly flirts with him; and tries to end the affair with Ayrs's wife. While packing his things to leave Ayrs, he discovers the second half of The Pacific Journal of Adam Ewing. After embarrassing himself with the discovery that Ayr's daughter was in love with another person altogether, Frobisher secludes himself in a hotel to finish the Sextet, and ultimately decides, with his magnum opus finished and his life now empty of meaning, to kill himself. Before committing suicide in a bathtub, he writes a last letter to Sixsmith and includes his Sextet and The Pacific Journal of Adam Ewing.
The Pacific Journal of Adam Ewing (Part 2)
Ewing visits the island of Raiatea, where he observes missionaries oppressing the indigenous peoples. On the ship, he falls further ill, and realizes at the last minute that Dr. Goose is poisoning him to steal his possessions. He is rescued by Autua, and resolves to join the abolitionist movement. In conclusion (of his own journal and of the book), Ewing writes that history is governed by the results of vicious and virtuous acts precipitated by belief: wherefore "a purely predatory world shall consume itself" and "The devil take the hindmost until the foremost is the hindmost", and imagines his father-in-law's response to his becoming an abolitionist, as a warning that Adam's life would amount to one drop in a limitless ocean; whereas Ewing's proposed reply is: "Yet what is any ocean but a multitude of drops?".