This film follows the stories of six people's "souls" across time, and the stories are interweaved as they advance, showing how they all interact. It is about how the people's lives are connected with and influence each other.
The first storyline follows a lawyer named Adam Ewing (Jim Sturgess) in the early 1800s, whose family is in the slave trade. He has been sent to the Pacific to arrange a contract for some Maori slaves with a slave trader from that area. During his return voyage home, Ewing saves the life of a native man named Autua (David Gyasi) who is a runaway slave stowing away on the ship. Ewing also realizes he is being poisoned by a doctor he trusted, Dr. Henry Goose (Tom Hanks), who is robbing Ewing as he gets sicker and sicker. Autua saves Ewing's life and his views of the natives are changed in important ways as he comes to know the man. Adam Ewing's journal, which chronicled his ordeal and rescue by a runaway slave, are later published into a book which is discovered by the next character in the storyline. Ewing and his wife decide to quit the family slave trade and move east to become abolitionists.
The second storyline follows the tragically short life of a talented young wannabe composer in the 1930's named Robert Frobisher (Ben Whishaw) who finagles himself into a position aiding an aging composer, Vyvyan Ayrs (Jim Broadbent). While working for Ayrs, Robert Frobisher begins reading the published chronicle of Adam Ewing's journal which he has found among the many books at Ayrs's mansion. He never finishes reading the journal and it is unclear what effect it has on the creation of his own musical composition. Robert enters a sexual relationship with Ayrs' wife, which, along with Ayrs' own arrogance and presumption of superiority of position and class, tears him and Ayrs apart. Ayrs threatens to ruin Frobisher's already rickety reputation when he encounters Frobisher's own work, the Cloud Atlas Sextet. Ayrs forces Frobisher to accept second place in the credit for the Sextet. Frobisher inadvertently shoots Ayrs during an argument then flees. When Ayrs survives the shooting, and sets police after him, he realizes he is facing utter ruin, as Ayrs threatened. Frobisher completes the Sextet, then sends it to his lover and friend, a Cambridge student, Rufus Sixmith (James D'Arcy) and commits suicide. Rufus Sixsmith meets the main character in the third storyline much later in his life, and we discover Robert Frobisher's Cloud Atlas Sextet has been recorded into an album and although it is an obscure recording, it has clearly affected people's lives.
The third storyline is about a journalist in the 1970's named Luisa Rey (Halle Berry). She meets Rufus Sixsmith in a chance encounter while being stuck on a broken elevator. Sixsmith by now is now a renowned physicist. After leaving the elevator, Sixsmith later attempts to re-contact Rey and reveal that there is a conspiracy afoot to cover up a report about the flaws in the design of a nuclear power reactor. When she is about to meet-up with Sixsmith, she finds him just recently dead, an apparent suicide. Her journalistic instincts kick in, telling her there is more to the story than a man committing suicide, and she discovers that a report on the reactor written by Sixsmith can reveal the terrible secret. Along with the report, Rey also finds a collection of letters written from Frobisher to Sixsmith many years earlier while Frobisher was working on the Cloud Atlas Sextet composition. A scientist named Isaac Sachs (Tom Hanks) meets Rey and helps her. The CEO, Lloyd Hooks (Hugh Grant) sends his head of security, Joe Napier (Keith David) and his agent, Bill Smoke (Hugo Weaving) to stop her. Smoke has already killed Sixsmith, and then Sachs, and attempts to kill Rey as she gets closer and closer to the truth. Smoke is stopped in the end by Joe Napier. As Napier and Rey escape death by the hands of Smoke, Luisa Rey publishes an article leading to the shutdown of the reactor after revealing the contents of the Sixsmith Report.
The fourth storyline is a modern-day tale of Timothy Cavendish (Jim Broadbent), the owner of a small publishing company, who has published a small biographical book by a lowlife thug. While the book has literally no hope of making much, if any, money, this changes when the author-thug kills a critic of his book by throwing him off a balcony to his death. Suddenly the book has legs and Cavendish is rolling in money from royalties. When friends of the thug come looking for his royalties, Cavendish is put in a tight situation, as he doesn't have the money they are demanding, and clearly the hooligans aren't particularly constrained by the law. While traveling by train to the hide-out address his brother recommended, Cavendish is seen reading a manuscript that was sent to him. The manuscript is titled, "Half Lives - The First Luisa Rey Mystery" and is the romanticized version of the third storyline. He arrives at the "hotel" his brother sent him to, which, only the next day is revealed to be a nursing home for the elderly. Residents are treated as prisoners, and each attempt to get out is stopped by the staff (which is revealed to be the nursing home's primary purpose, to lock up troublesome relatives). With the assistance of three other residents, Cavendish eventually creates an escape plan and they manage to escape. Once he makes good on his escape, he writes a best-selling tale of his adventures, which is later made into a biopic.
The fifth storyline is about Sonmi-451 (Doona Bae), a clone bred for work in a Papa Song fast-food restaurant in Korea (now called Neo Seoul) in the far future. In this stark future, she lives in a day-to-day world, each day identical to the next, existing only to serve food to "consumers." But her limited life is revealed to be less than she is capable of when another of the clones inadvertently awakens her from her daily slumber. Sonmi-451 through chance, discovers a fragment of the biopic film of "The Ordeal of Timothy Cavendish" on a cell-phone/PDA left at the Papa's Song fast-food restaurant. This film lays the seeds of the never-ending struggle against injustice. She starts to question all the things she has seen and experienced, including the believed purpose of her existence, from which other clones, and eventually she, will "ascend" after eleven years of work. When her friend, the other clone, is killed, she meets a man named Hae-Joo Im, who it is revealed was behind her friend, and then her, being exposed to something more than their day-to-day existence. They have been attempting to prove that the clones are the equal of "naturally born" humans ("purebloods"), hearkening back to the days of slavery. Hae-Joo rescues her from her life in the restaurant and begins teaching her about the outside world as well as philosophy, art, and "higher values". When they are captured by the authorities, he escapes, then rescues her from the authorities. He reveals he is actually a former member of the military who has become a member of a revolutionary organization, the Union, taking action against the oppressive government, that wishes to free the clones in Neo Seoul. Somni-451 is proof that the clones are capable of being more than mere slaves. He takes Sonmi-451 to meet the other revolutionaries, who arrange for her to learn what "ascension" really is, on a ship where they massacre the clones, only to reprocess them and use their bodies to feed the still-functioning clones. She agrees to assist the revolutionaries, knowing it means capture and death, by writing a Manifesto. They capture a broadcast facility, and reveal the truth, not just to all earth but to the offworld colonies as well. All of the revolutionaries, including Hae-Joo, but except Sonmi-451, are killed holding off the government's agents so that she can keep broadcasting her Manifesto. Sonmi-451 reveals all the above while being questioned by an agent of the government, who asks her why she did it all, when the government will make everyone believe it was false. She acknowledges that she goes to her execution calmly, believing that death is only a door, and knowing that one person -- her interviewer -- knows it is true, and that it will not be possible to suppress the Truth.
The sixth and final storyline is about Zachry (Tom Hanks) who is a tribesman living in a low-tech post-apocalyptic Hawaii, 100 years after Neo Seoul has been swallowed by the sea. His people revere Sonmi and believe her to be holy. A member of a far more advanced group of people called the Prescients named Meronym (Halle Berry) asks to live with their tribe. Zachry's sister takes her in, and their relationship grows. Zachry is harboring his own secret, that he hid in cowardly shame while barbarians called the Kona killed his brother-in-law and his nephew. People suspect him, and he is largely an outcast, but his sister and his niece still accept and love him. Meronym wishes to cross the mountains to get to a place she believes is inland, but it is an area fraught with superstitious dread, and no one will take her there. When Zachry's beloved niece is taken fatally ill, and he realizes only Meronym has the ability to heal and save her, he agrees to lead her up the mountains to where she wants to go in exchange for Meronym's assistance. Zachry's fears, personified by his tribe's belief in a god of Death named Old Georgie, whisper to him that he must kill Meronym, that he is risking his tribe for an outsider. He rejects the impulses, seeing in Meronym something more and better than his fears can destroy. Meronym and Zachry succeed in reaching a large facility, and he is again pushed by Old Georgie to kill Meronym, and he again resists, but barely. Meronym reveals to Zachry that the world is dying, that all humans, even the Prescients, are doomed, unless they can reach the offworld colonies, if they still exist at all (most of the Prescients believe them to be dead and Meronym on a likely fool's errand). Meronym reveals that the place they are at is the same broadcast facility that Sonmi used to transmit her manifesto. She explains to him that his beliefs are not entirely true, that Sonmi was a human, not a goddess, and shows him pictures and things that prove it. They return to the valley of Zachry's clan, only to see smoke in the distance. Zachry realizes his tribe is under attack by the barbarian Kona and runs ahead to assist. When he arrives, everyone in his tribe is dead, and all the Kona appear to be gone. He sees his sister's dead body, then runs to their hut to find his niece. There he finds one lone barbarian lying in a drunken stupor, and he kills him in rage. He hears a noise and finds his niece hiding in a small niche. At the same time, the barbarians return looking for their clansman, and, seeing his horse outside the hut, begin to investigate. They see him lying there, throat freshly cut, and begin to search the hut for whoever killed him. Zachry and his niece flee, with the Kona in hot pursuit. The Kona catch up to them in the same woods where he hid in cowardice as his brother-in-law was killed. As he is about to die, in much the same place and position as his brother died (the story thus coming full circle), Meronym steps up from the place he hid in cowardice. She uses her advanced weapons and risks her own life to save him, and they kill the half-dozen Kona together. Meronym signals for her own people, and they accept Zachry and his niece in as their own, with Meronym's urging.
Finally, it's shown that Zachry has been telling his tale to a large group of children, and that he married Meronym, and that the offworld colonies heard their broadcast, and came to rescue the survivors... and that he and Meronym are on another world entirely.
One of the most important quotes in the film comes from Sonmi-451:
"Our lives are not our own. From womb to tomb, we are bound to others, past and present. And by each crime and every kindness, we birth our future."