Arthur Dent, a decidedly average Englishman, has his day—and entire life—upended when he discovers his best friend, Ford Prefect, is an alien from a star system somewhere in the vicinity of Betelgeuse, and that Earth is about to be demolished to make way for a hyperspace bypass. Moments before the planet's destruction, Ford hustles Arthur onto a passing spacecraft, the Heart of Gold, effectively rescuing him from annihilation. The ship, commandeered by the peculiar and somewhat frivolous President of the Galaxy, Zaphod Beeblebrox, is equipped with a revolutionary Improbability Drive that allows it to traverse vast interstellar distances in a heartbeat.

On board, Arthur and Ford are further joined by Trillian, the only other human survivor from Earth who had previously left the planet with Zaphod, and a depressed robot named Marvin. The motley crew embarks on a wild and whimsical journey through space, guided by the "Hitchhiker's Guide to the Galaxy", a digital encyclopedia of sorts that offers advice, information, and commentary on the universe. Together, they encounter a variety of bizarre creatures and situations, including a pair of philosophically inclined mice and an entire planet dedicated to manufacturing luxury starships. As the unlikely heroes dart from one misadventure to the next, they seek the answers to some of life's most perplexing questions and the ultimate question of life, the universe, and everything—with quite unexpected results.