"Born Granville G. Withers in Pueblo, Colorado, Withers worked as an oil company salesman and newspaper reporter before breaking into films near the end of the silent era." His more-than-30-year acting career took off in the late 1920s. While in his twenties, his hairy-chested rugged good looks made him leading man over rising talent James Cagney in Other Men's Women (1931).

The comedy short So Long Bill (1926) marked Withers' film debut.

In 1930, at twenty-six, he eloped to Yuma, Arizona, with 17-year-old Actress Loretta Young. The marriage was widely reported and ended in annulment in 1931. The annulment took place just as their second movie together, titled Too Young to Marry, was released. He was also married to Gladys Joyce Walsh.

Taller than John Wayne and just as tough, yet capable of sensitivity, his early roles for Warner Brothers brought him his highest accolades. Withers' early work had him opposite such major talent as W. C. Fields, Buster Keaton, Boris Karloff, Mae West, and Shirley Temple. Appearing in The Red-Haired Alibi (1932) with Temple, he played the role of her first on-screen parent.

Starring roles in major pictures later dwindled to supporting parts, mainly as villains in B-movies and serials. Notable exceptions included a 12-part Jungle Jim movie serial (1937), starring Withers and released by Universal Pictures and the recurring role of the brash police Captain Bill Street in the Monogram Pictures series Mr. Wong, starring Boris Karloff, beginning in 1938. He was under a Republic Pictures contract from February 1944 through April 1954. Withers' credits at Republic total about sixty films from 1937 to 1957.

After 1940, he was a character actor and a popular Western tough guy. He took numerous supporting roles in television as his popularity in films waned. He guest-starred as baseball Coach Whitey Martin in the 1956 episode "The Comeback" of the religion anthology series Crossroads. He was cast as Gus Andrews and Miles Breck, respectively, in two episodes, "The time for All Good Men" (1957) and "King of the Frontier" (1958), on the ABC western series The Life and Legend of Wyatt Earp starring Hugh O'Brian.

Some of Withers' later screen appearances were arranged through the auspices of his friends John Ford and John Wayne. He appeared in nine movies with John Wayne, including Fort Apache (1948) and Rio Grande (1950).

Wayne was best man at Withers' fifth marriage, to 24-year-old Cuban-born Actress Estelita Rodriguez (Rio Bravo) in January 1953 in Reno, Nevada. They too resided in the San Fernando Valley on Woodcliff Avenue in Sherman Oaks, California. Estelita began a nightclub singing career at the end of her Republic contract. The marriage was not a happy one. They divorced in 1955. A noticeable weight gain became apparent in his films as his career progressed. In later years, back problems were one of his health issues.

In 1958, Withers portrayed the wealthy rancher Sam Barton in the episode "The Return of Dr. Thackeray" of CBS's Have Gun - Will Travel. In the segment, lead character Paladin, played by Richard Boone, comes to the assistance of a physician friend portrayed by June Lockhart. Dr. Thackeray diagnoses a cook with smallpox and worries that the disease will infect the ranch hands when Barton refuses to permit his men to be vaccinated. Singer Johnny Western, who performed the Have Gun - Will Travel theme song, appeared in this episode as an angry gunslinger. Withers also appeared in two other Have Gun – Will Travel episodes. That year he played Charles Stewart Brent, owner of the Brent Building in Los Angeles, where Perry Mason had his office, and the defendant in the Perry Mason episode "The Case of the Gilded Lily."

Withers died in his apartment at age 55. With failing health, he committed suicide by overdosing on barbiturates on March 27, 1959. Withers left a suicide note that read, "Please forgive me, my family. I was so unhappy. It's better this way." He is interred at Forest Lawn Memorial Park in Glendale, California.