The Rise of the West, winner of the National Book Award for history in 1964, is famous for its ambitious scope and intellectual rigor. In it, McNeill challenges the Spengler-Toynbee view that a number of separate civilizations pursued essentially independent careers, and argues instead that human cultures interacted at every stage of their history. The author suggests that, from the Neolithic beginnings of grain agriculture to the present, major social changes in all parts of the world were triggered by new or newly important foreign stimuli, and he presents a persuasive narrative of world history to support this claim.

In a retrospective essay titled "The Rise of the West after Twenty-five Years," McNeill shows how his book was shaped by the time and place in which it was written (1954-63). He discusses how historiography subsequently developed and suggests how his portrait of the world's past in The Rise of the West should be revised to reflect these changes.