Puzo was born into a family of Sicilian immigrants living in the "Hell's Kitchen" neighborhood of Manhattan, New York City. Many of his books draw heavily on this heritage. He joined the United States Army Air Forces in World War II and was stationed in Asia and Germany. His first book, The Dark Arena was published in 1955.

His most famous work, The Godfather, was first published in 1969 after hearing anecdotes of Mafia organizations during his time in pulp journalism.

The Godfather was later developed into a trilogy of popular and highly acclaimed films directed by Francis Ford Coppola released in 1972, 1974 and 1990. In addition to co-writing the screenplay with Coppola, Puzo was also involved with writing the disaster film Earthquake and 1978's Superman: The Movie.

Puzo never saw his last book Omertà published, but the manuscript was finished, and thus it became his last work. In a review originally published in the San Francisco Chronicle, Jules Siegel, who worked closely with Puzo at Magazine Management Company, expressed doubts that he actually ever finished the novel, and that it might have been completed by "some talentless hack."