Cloud Atlas had positive reviews from most critics, who felt that it managed to successfully interweave its six stories. The BBC's Keily Oakes said that although the structure of the book could be challenging for readers, "David Mitchell has taken six wildly different stories ... and melded them into one fantastic and complex work." Kirkus Reviews called the book "sheer storytelling brilliance." Laura Miller of The New York Times compared it to the "perfect crossword puzzle," in that it was challenging to read but still fun. The Observer's Hephzibah Anderson called the novel "exhilarating" and commented positively on the links between all six stories. Author and Booker Prize winner A. S. Byatt in a review for The Guardian wrote that it gives "a complete narrative pleasure that is rare." The Washington Post's Jeff Turrentine called it a "highly satisfying, and unusually thoughtful, addition to the expanding 'puzzle book' genre." In its "Books Briefly Noted" section, The New Yorker called the novel "virtuosic." Marxist literary critic Fredric Jameson viewed the novel as a new, science fiction-inflected variation on the historical novel now "defined by its relation to future fully as much as to past." Richard Murphy says in the Review of Contemporary Fiction that Mitchell has taken core values from his previous novels and built upon them.
Criticism focused on the book's failure to meet its lofty goals. F&SF reviewer Robert K. J. Killheffer praised Mitchell's "talent and inventiveness and willingness to adopt any mode or voice that furthers his ends," but noted that "for all its pleasures, Cloud Atlas falls short of revolutionary." The Daily Telegraph gave the novel a mixed review, focusing on its clashing themes, with Theo Tait noting: "In short, Cloud Atlas spends half its time wanting to be The Simpsons and the other half the Bible."