Vaughn was born in New York City to showbiz parents Marcella Frances (née Gaudel), a stage actress, and Gerald Walter Vaughn, a radio actor. He was raised in an Irish Catholic family, living with his grandparents in while his mother traveled. He attended North High School and later enrolled in the University of Minnesota as a journalism major. He quit after a year and moved to with his mother. He enrolled in Los Angeles City College, then transferred to Los Angeles State College of Applied Arts and Sciences, where he earned a Master's degree in theater. Continuing his higher education even through his successful acting career, Vaughn earned a Ph.D. in communications from the University of Southern California, in 1970. In 1972, he published his dissertation as the book Only Victims: A Study of Show Business Blacklisting.

Vaughn made his television debut on the November 21, 1955 "Black Friday" episode of the American TV series Medic, the first of more than two hundred episodic roles by mid-2000. He appeared with Virginia Christine in the episode "The Twisted Road", the story of a troubled brother-sister relationship which results in the murder of a young woman, of the western syndicated series, Frontier Doctor, starring Rex Allen in the title role.

His first film appearance was as an uncredited extra in The Ten Commandments (1956), playing a golden calf idolater and also visible in a scene in a chariot behind that of Yul Brynner. Vaughn's first credited movie role came the following year in the Western Hell's Crossroads (1957), in which he played the real-life Bob Ford, the killer of outlaw Jesse James. After being seen by Burt Lancaster in Calder Willingham's play End as a Man, Vaughn was signed to a contract with Lancaster's film company and was to have played the Steve Dallas role in The Sweet Smell of Success but was drafted into the Army before he could begin the film.

Vaughn's first notable appearance was in The Young Philadelphians (1959) for which he was nominated for an Academy Award for Best Supporting Actor and a Golden Globe Award for Best Supporting Actor - Motion Picture. Next he appeared as gunman Lee in The Magnificent Seven (1960), a role he essentially reprised 20 years later in Battle Beyond the Stars (1980), both films being adaptations of filmmaker Akira Kurosawa's 1954 Japanese samurai epic, Seven Samurai. Vaughn played a different role, Judge Oren Travis, on the 1998-2000 syndicated TV series The Magnificent Seven. Vaughn is the only surviving member of the title cast of the original 1960 film (although Eli Wallach, who portrayed the villain Calvera, Rosenda Monteros, who played Petra, and Rico Alaniz, who played Sotero, are still living).

In the 1963-1964 season, Vaughn appeared in The Lieutenant as Captain Raymond Rambridge alongside Gary Lockwood, the Marine second lieutenant at Camp Pendleton. His dissatisfaction with the somewhat diminished aspect of the character led him to request an expanded role. During the conference, his name came up in a telephone call and he ended up being offered a series of his own - as Napoleon Solo, title character in a series originally to be called Solo, but which became The Man From U.N.C.L.E. after the pilot was reshot with Leo G. Carroll in the role of Solo's boss. This was the part that would make Vaughn a household name even behind the Iron Curtain (detailed in the interviews included in the Man From U.N.C.L.E. boxed briefcase set). Earlier, Vaughn had guest starred on Lockwood's ABC series Follow the Sun.

From 1964 to 1968, Vaughn played Solo with British co-star David McCallum playing his fellow agent Illya Kuryakin. This production spawned a spin-off show, large amounts of merchandising, overseas theatrical movies of re-edited episodes, and a sequel The Return of the Man from U.N.C.L.E. - The Fifteen-Year-Later Affair. In the year the series ended, Vaughn landed a large role playing Chalmers, an ambitious California politician in the film Bullitt starring Steve McQueen; he was nominated for a BAFTA Award for Best Supporting Actor for this role.

Vaughn continued to act, in television and in mostly B movies. He starred in two seasons of the British detective series The Protectors in the early 1970s, and a decade later starred with friend George Peppard in the final season of The A-Team. According to Dirk Benedict, Vaughn was actually added to the cast of that show because of his friendship with Peppard. It was hoped Vaughn would help ease tensions between Mr. T and Peppard.

In 2004, after a string of guest roles on series such as Law & Order, in which he had a recurring role during season eight, Vaughn experienced a resurgence. He began co-starring in the British series Hustle, made for BBC One, which was also broadcast in the United States on the cable network AMC. In the series, Vaughn plays elder-statesman con artist Albert Stroller, a father figure to a group of younger grifters. In September 2006, he guest-starred in Special Victims Unit.

Since the mid-1990s, Vaughn has been a spokesman in a set of generic advertisements for various personal injury law firms around the U.S.A. and Canada. The television commercial features Vaughn urging injured complainants to "...tell the insurance companies you mean business."

Vaughn also appeared as himself narrating and being a character in a radio play broadcast by BBC Radio 4 in 2007 about making the film The Bridge at Remagen in Prague, Czechoslovakia, during the Russian invasion of 1968.

Frequent references are made to his playing Napoleon Solo and the character's great spying abilities.

Vaughn is a long-time member of the Democratic Party. His family was also Democratic and was involved in politics in Minneapolis, Minnesota. and early in his career, he was described as a "liberal Democrat". He was the chair of the California Democratic State Central Committee speakers bureau and actively campaigned for candidates in the 1960s.

Vaughn was active in the Vietnam War-era peace group, Another Mother For Peace, and, with Dick Van Dyke and Carl Reiner, was a founder of Dissenting Democrats. Early in the 1964 presidential election, they supported the candidacy of Eugene McCarthy, mentioned for the vice presidency. The choice was prophetic, as McCarthy was not selected for the second position but did seek the presidency in 1968. Vaughn was also reported to have political ambitions of his own, but in a 1973 interview, he denied having had any political aspirations.

He is also the voice and face of various law firms across the northeast, such as that of Mark E. Solomone.

Vaughn does not support Barack Obama, and described him as "not up to the job" in March 2009.

In his memoir, A Fortunate Life, Vaughn recalls watching his good friend Jack Nicholson stumble his way through a scene of Bus Stop in a mid-1950s acting class without the "confidence" to carry it off. "Nicholson declared, 'Vaughnie, I'm going to give myself two more years in this business. Then I'm going to look for another way to make a living.' 'Hang in there, Jack,' Vaughn told him. 'You're too young to quit.'"

Vaughn married actress Linda Staab in 1974. They appeared together in a 1973 episode of The Protectors, called "It Could Be Practically Anywhere on the Island", in which Staab guested as a ditzy American whose dog was stolen. Vaughn's character Harry Rule stepped in to find the dog. They have adopted two children, Cassidy (b. 1976) and Caitlin (b. 1981). They reside in Ridgefield, Connecticut. They also have a Labrador Retriever mix named Sam, which was adopted after the death of their previous dog, a Bichon Frisé named Peaches.

Stage

• He appeared in the United States in the early 1970s as the lead actor in the Tom Stoppard play, The Real Inspector Hound.
• Has portrayed Presidents Franklin D. Roosevelt and Harry S. Truman in addition to Woodrow Wilson, in the 1979 television miniseries Backstairs at the White House. He additionally played Roosevelt on TV, in the 1982 telefilm FDR: That Man in the White House).

Film

• Hell's Crossroads (1957)
• No Time to be Young (1957)
• Teenage Cave Man (1958)
• Good Day for a Hanging (1958)
• The Young Philadelphians (1959)
• The Magnificent Seven (1960)
• The Spy with My Face (1965)
• The Venetian Affair (1967)
• Bullitt (1968)
• The Bridge at Remagen (1969)
• The Mind of Mr. Soames (1970)
• Julius Caesar (1970)
• Clay Pigeon (1971)
• The Towering Inferno (1974)
• Black Moon Rising (1976)
• Starship Invasions (1977)
• Good Luck, Miss Wyckoff (1979)
• Battle Beyond the Stars (1980)
• Fukkatsu no hi (1980)
• Hangar 18 (1980)
• S.O.B. (1981)
• Demon Seed (1977; voice of Proteus IV, uncredited)
• Superman III (1983)
• Hour of the Assassin (1985)
• The Delta Force (1986)
• Renegade (1987)
• Killing Birds (1987)
• Bud the C.H.U.D. (1989)
• Witch Academy (1993)
• Joe's Apartment (1996)
• BASEketball (1998)
• Pootie Tang (2001)

Television

• Gunsmoke guest appearance as Kid in "Cooter" (1956)
• State Trooper as Mitch in "Another Chance" (1956)
• Frontier as Cliff in "The Return of Jubal Dolan" (1956)
• Father Knows Best as Mr Beekman in "Betty Goes Steady" episode (1956)
• The Rifleman as Dan Willard in "The Apprentice Sheriff" episode (1958)
• Alfred Hitchcock Presents in "Dry Run" episode (1959)
• The DuPont Show with June Allyson as Dr. Collins in "Emergency" (1960)
• The Corruptors!, as Lace in the episode "To Wear a Badge", December 1, 1961
• Bonanza (guest appearance as "Luke", a wanted murderer)
• The Eleventh Hour (2 episodes, 1962—1963)
• The Lieutenant
• Solo (pilot episode for the below)
• The Man from U.N.C.L.E.
• The Protectors
• Captains and the Kings 1976 TV Miniseries (role of Charles Desmond)
• Washington: Behind Closed Doors 1977 - Emmy-winning role
• Backstairs at the White House 1979 TV Miniseries (Woodrow Wilson)
• Inside the Third Reich (1982 telefilm)
• Murrow (1986)
• Columbo (two guest appearances: One as a victim, the other as the murderer)
• Hunter (1989 - City Under Siege 3 episodes as Deputy Chief Curtis Moorehead)
• Murder, She Wrote (three guest appearances)
• Emerald Point N.A.S.
• The Return of the Man from U.N.C.L.E. (telefilm)
• Centennial later part of the miniseries
• The A-Team
• Escape to Witch Mountain 1995 made-for-television film
• The Nanny (guest appearance as Maxwell Sheffield's father)
• Hustle (2004—Present)
• Law & Order
• Little Britain USA (1 episode, 2008)

Books