Vaughn was born in New York City to Roman Catholic showbiz parents, Walter and Marcella Vaughn. Vaughn's first notable appearance was in The Young Philadelphians (1959) for which he was nominated for the Academy Award. Next he appeared as one of The Magnificent Seven, a role he parodied twenty years later in Battle Beyond the Stars.

Starting in 1964, he starred as "Napoleon Solo", the eponymous Man from U.N.C.L.E., along with British co-star David McCallum. He continues to act in film and television, most recently appearing in the 2004 BBC series, Hustle. He has also done a series of television commercials for different law offices across the nation, such as in Lexington, Kentucky and Knoxville, Tennessee.

He married the actress Linda Staab in 1974 and they have two children, Cassidy (born 1975) and Caitlin.

Politically, he is a moderate Democrat. He earned a PhD in Communications from the University of Southern California and published his dissertation as the politically-charged book Only Victims: A Study of Show Business Blacklisting in 1972.

On stage:

Portrayed Presidents Franklin D. Roosevelt and Harry S. Truman. On screen:

The Young Philadelphians The Magnificent Seven Bullitt The Towering Inferno S.O.B. Demon Seed (voice, uncredited) Superman III (Ross Webster) The Bridge at Remagen BASEketball Pootie Tang Zombie 5: Killing Birds On TV: