Walker was born in Hartford, Illinois. He left school to work at a factory and on a river boat, then joined the United States Merchant Marine at the age of seventeen in the last months of World War II. After leaving the Merchant Marine, he labored at odd jobs in Brownwood, Texas, Long Beach, California, and Las Vegas, where he worked as a doorman at the Sands Hotel.
In Los Angeles, he was hired by Cecil B. DeMille to appear in The Ten Commandments. A friend in the film industry helped get him a few bit parts that brought him to the attention of Warner Bros., who were in the process of developing a western style television series.
Walker's good looks and physique—he is one-quarter Cherokee descent, stands 6 ft 6 in (198 cm), with a 48in chest and a 32in waist —landed him an audition and he won the lead role. Billed as "Clint" Walker, he was cast as Cheyenne Bodie, a cowboy hero set in the post American Civil War era. Although the series regularly capitalized on Walker's rugged frame with frequent bare-chested scenes, it was well written and acted. It proved hugely popular for eight seasons on the ABC television network.
Walker then played roles in several big screen films, including a trio of westerns for Gordon Douglas - Fort Dobbs in 1958, Yellowstone Kelly in 1959, and Gold of the Seven Saints in 1961, the comedy Send Me No Flowers in 1964, The Night of the Grizzly in 1966, and the very successful war drama The Dirty Dozen in 1967.
During the 1970s he returned to television, starring in a number of made-for-TV western films as well as a short-lived series in 1974 called Kodiak. In 1998, he acted the voice of Nick Nitro in Small Soldiers.