After screen tests at 20th Century-Fox and Columbia Pictures, Clarke landed a berth as a contract player at RKO Radio Pictures. His first credited role was The Falcon in Hollywood (1944), then went on to play small roles in The Body Snatcher (1945), Bedlam (1946), and Dick Tracy Meets Gruesome (1947). When RKO dropped his option three years later, he began freelancing. In the 1950s, he appeared in many classic science fiction films, including The Man from Planet X (1951), Captain John Smith and Pocahontas (1953) as John Rolfe, The Incredible Petrified World (1957), The Astounding She-Monster (1957), and The Hideous Sun Demon (1959), which Clarke wrote, directed and produced. Clarke revealed in his 1996 autobiography To 'B' or Not to 'B' (co-written by Tom Weaver) that he made The Hideous Sun Demon for less than $50,000, including $500 for the rubberized lizard suit he wore. He shot the movie over 12 weekends to get two days' use of rental camera equipment for one day's fee. The Hideous Sun Demon was featured in the 1982 movie It Came from Hollywood, and with Clarke's permission, was re-dubbed into the 1983 comedy What's Up, Hideous Sun Demon (aka Revenge of the Sun Demon) featuring the voices of Jay Leno and Cam Clarke reprising his father's role.

From the 1950s through the 1980s, he regularly appeared on television series, including appearing on The King Family Show (1965),. He made two guest appearances on Perry Mason, including the role of circus co-owner and murderer Jerry Franklin in the 1960 episode, "The Case of the Clumsy Clown". Other television appearances included The Lone Ranger, The Cisco Kid, Men Into Space,The Man and the Challenge, Hawaiian Eye, 77 Sunset Strip, Wendy and Me, General Hospital, Marcus Welby, M.D., Dragnet, Adam-12, Sea Hunt, Ripcord, Sky King, Checkmate, M Squad, Daktari, Baa Baa Black Sheep, Hawaii Five-O, Tabitha, Trapper John, M.D., Fantasy Island, Dallas, Simon & Simon, Knight Rider, Murder She Wrote, Matt Houston, Hotel, Dynasty, Falcon Crest, and dozens of others. The 1997 biographical documentary Lugosi: Hollywood's Dracula featured narration which he provided. Clarke's last appearance was in the movie The Naked Monster, a send-up of the classic science fiction films of the 1950s, in 2005.

Clarke married Alyce King in 1956. They remained wed until her death in 1996. He was the father of actor and voice Artist Cam Clarke.

In the mid-1960s, he served as spokesperson for a furniture and appliance store chain called Gold's Giant Stores. His autobiography, To "B" or Not to "B": A Film Actor's Odyssey, was published in 1996.

Clarke died June 11, 2005, at his home in Valley Village, California from complications of diabetes. He was 85.

Clarke was born and raised in Oklahoma City, Oklahoma. He decided at an early age that he wanted to be an actor, but nevertheless suffered from stage fright in his first school productions. He attended Kemper Military School and College, planning to make a career in the Service, but dropped out after his asthma prevented his serving in World War II. He later attended the University of Oklahoma, where he acted in radio plays, and the University of Wisconsin–Madison, where he appeared on stage. He did not graduate, but hitched a ride to California to try to break into the motion picture Business.