Began his career as an assistant on numerous Italian productions of the late 1940s and early 50s and came to prominence in the 1960s, when he revitalized the western genre with a series of gritty, semi-satirical homages known as "spaghetti westerns." "The cowboy picture has got lost in psychology," he said; "The West was made by violent uncomplicated men, and it is this strength and simplicity that I try to recapture in my pictures."

Leone's gun-and-sun operas, with their spasmodic violence, striking and insistent use of closeups (often immediately following panoramic establishing shots) and motif-laden Ennio Morricone scores, provided employment for a number of American actors, most notably Lee Van Cleef and Clint Eastwood, who starred as the laconic anti-hero of "A Fistful of Dollars" (1964), "For a Few Dollars More" (1966) and "The Good, the Bad, and the Ugly" (1966). Leone's last major project was "Once Upon a Time in America" (1984), a bloody tribute to the American gangster film. Though praised at the Cannes Film Festival and across Europe, it was severely cut for US release to an extent which made it almost incomprehensible. Father Vincenzo Leone was a noted silent film director.