Puzo was born in a poor family of Neapolitan immigrants living in the Hell's Kitchen neighborhood of New York. Many of his books draw heavily on this heritage. After graduating from the City College of New York, he joined the United States Army Air Forces in World War II. Due to his poor eyesight, the military did not let him undertake combat duties but made him a public relations officer stationed in Germany. In 1950, his first short story, The Last Christmas, was published in American Vanguard. After the war, he wrote his first book, The Dark Arena, which was published in 1955.
At periods in the 1950s and early 1960s, Puzo worked as a writer/editor for publisher Martin Goodman's Magazine Management Company. Puzo, along with other writers like Bruce Jay Friedman, worked for the company line of men's magazines, pulp titles like Male, True Action, and Swank. Under the pseudonym Mario Cleri, Puzo wrote World War II adventure features for True Action.
Puzo's most famous work, The Godfather, was first published in 1969 after he had heard anecdotes about Mafia organizations during his time in pulp journalism. He later said in an interview with Larry King that his principal motivation was to make money. He had already, after all, written two books that had received great reviews, yet had not amounted to much. As a government clerk with five children, he was looking to write something that would appeal to the masses. With a number one bestseller for months on the New York Times Best Seller List, Mario Puzo had found his target audience. The book was later developed into the film The Godfather, directed by Francis Ford Coppola. The movie received 11 Academy Award nominations, winning three, including an Oscar for Puzo for Best Adapted Screenplay. Coppola and Puzo collaborated then to work on sequels to the original film, The Godfather Part II and The Godfather Part III.
Puzo wrote the first draft of the script for the 1974 disaster film Earthquake, which he was unable to continue working on due to his commitment to The Godfather Part II. Puzo also co-wrote Richard Donner's Superman and the original draft for Superman II. He also collaborated on the stories for the 1982 film A Time to Die and the 1984 Francis Ford Coppola film The Cotton Club.
Puzo never saw the publication of his penultimate book, Omertà, but the manuscript was finished before his death, as was the manuscript for The Family. However, in a review originally published in the San Francisco Chronicle, Jules Siegel, who had worked closely with Puzo at Magazine Management Company, speculated that Omertà may have been completed by "some talentless hack." Siegel also acknowledges the temptation to "rationalize avoiding what is probably the correct analysis -- that [Puzo] wrote it and it is terrible."
Puzo died of heart failure on July 2, 1999 at his home in Bay Shore, Long Island, New York. His family now lives in East Islip, New York.