Boone was married three times: to Jane Hopper (1937–1940), Mimi Kelly (1949–1950), and Claire McAloon (from 1951 until his death). His son with Claire McAloon, Peter, worked as a child actor in several of his father's Have Gun – Will Travel television shows.

Richard Boone graduated from Hoover High School in Glendale, California. He attended Stanford University in Palo Alto, California, where he was a member of Theta Xi fraternity. He dropped out prior to graduation and went to work in oil-rigging, bartending, painting, and writing. He joined the United States Navy in 1941 and served on three ships in the Pacific during World War II, seeing combat as an aviation ordnanceman, enlisted Naval Aircrewman and tail gunner on Grumman TBF Avenger torpedo bombers.

In his youth, Boone had attended the San Diego Army and Navy Academy in Carlsbad, California, where he was introduced to theatre under the tutelage of Virginia Atkinson. After the war, Boone used the G.I. Bill to study acting at the Actors Studio in New York. "Serious" and "methodical," Boone debuted on the Broadway theatrical scene in 1947 with the plays Medea, Macbeth (1948) and The Man (1950).

In 1950, Boone made his screen debut as a Marine officer in Milestone's Halls of Montezuma. In 1953, he played Pontius Pilate in the first Cinemascope film released, The Robe. He had only one scene in the film, in which he gives instructions to Richard Burton, who plays the centurion ordered to crucify Christ. When he was ordered to appear in another film for Fox made at the same time as The Robe, he ended his contract with the studio.

The six-foot-one-inch (1.85 m) actor continued to appear in movies, typically as the villain, including The Raid (1954), Man Without a Star (1955 King Vidor), The Tall T (1957 Budd Boetticher), The War Lord (1965 Franklin Schaffner), Hombre (1967 Martin Ritt), The Arrangement (1969 Elia Kazan), The Kremlin Letter (1970 John Huston), Big Jake (1971 George Sherman), The Shootist (1976 Don Siegel), and a second rendition of The Big Sleep (1978 Michael Winner).

In the 1960s and 1970s, Boone assisted the Israeli film industry at its inception. He appeared in the first Israeli-produced film shot outside Israel, the Western Madron (1970), with a story set in the American West of the 1800s. In 1979, he received an award from Israeli Prime Minister Yitzhak Rabin "for his contribution to Israeli cinema."

In 1965, he came in third in the Laurel Award for Rio Conchos in Best Action Performance; Sean Connery won first place with Goldfinger and Burt Lancaster won second place with The Train. Boone provided the character voice of the dragon Smaug in the 1977 animated film version of J.R.R. Tolkien's The Hobbit.

During the 1970s, he wrote a newspaper column for the St. Augustine Record called "It Seems To Me". He also gave acting lectures at Flagler College in 1972–1973. In his final role, Boone played Commodore Matthew C. Perry in The Bushido Blade.

Freeman, impressed by Boone's love of Hawaii, offered him the role of Steve McGarrett; Boone turned it down, however, and the role went to Jack Lord, who shared Boone's enthusiasm for the region, which Freeman considered vital. Coincidentally, Lord had appeared alongside Boone in the first episode of Have Gun – Will Travel, titled "Three Bells to Perdido." At the time, Boone had shot a pilot for CBS called Kona Coast, which he hoped CBS would adopt as a series, but the network went instead only with Hawaii Five-O.