Wills was born in 1902 in Seagoville near Mesquite in Dallas County, Texas. He was a performer from early childhood, forming and leading The Avalon Boys singing group in the 1930s. After appearing in a few westerns, he disbanded the group in 1938 and struck out on a solo acting career.
One of his more memorable roles was that of the distinctive voice of Francis the Mule in a series of popular films. Wills' deep, rough voice and Western twang were perfectly matched to the personality of the cynical, sardonic mule. As was customary at the time, Wills was given no billing for his vocal work, though he was featured prominently on-screen as blustery General Ben Kaye in the fourth entry, Francis Joins the WACS. He provided the deep voice for Stan Laurel's performance of "The Trail of the Lonesome Pine" in Way Out West (1937).
Wills was cast in numerous serious film roles, including that of Uncle Bawley in Giant (1956), which also features Rock Hudson, Elizabeth Taylor, and James Dean. Wills was nominated for Best Supporting Actor in 1960 for his role as Davy Crockett's companion "Beekeeper" in the film The Alamo. However, his aggressive campaign for the award was considered tasteless by many, including the film's star/director/producer, John Wayne, who publicly apologized for Wills. Wills' publicity agent, W.S. "Bow-Wow" Wojciechowicz, accepted blame for the ill-advised effort, claiming that Wills had known nothing about it. The Oscar was instead won by Peter Ustinov for his role as Lentulus Batiatus in Spartacus.
Wills was a poker player and a close friend of Benny Binion, the founder of the World Series of Poker and former owner of the Binion's Horseshoe Casino in Las Vegas, Nevada. Wills participated in the first World Series, held in 1970, and is seated in the center of the famous picture with a number of legendary players.
From 1961 to 1962, Wills starred in the short-run series Frontier Circus which aired for only one season on CBS. In 1966, Wills was cast in the role of a shady Texas rancher, Jim Ed Love, in the short-lived ABC comedy/western series The Rounders, with co-stars Ron Hayes, Patrick Wayne, and Walker Edmiston.
In 1963 and 1964, Wills joined fellow actors William Lundigan, Walter Brennan, and Efrem Zimbalist, Jr., in making appearances on behalf of U.S. Senator Barry M. Goldwater, the Republican nominee in the campaign against U.S. President Lyndon B. Johnson.
In 1968, however, Wills refused to support Richard M. Nixon for the presidency and served as master of ceremonies for George C. Wallace, former governor of Alabama, for the California campaign stops in Wallace's presidential campaign. With Walter Brennan, Wills was among the few Hollywood celebrities to endorse Wallace's bid against Nixon and Hubert H. Humphrey.
In 1968, he starred in Gunsmoke with James Arness in the episode "A Noose for Dobie Price" where he played Elihu Gorman, a former outlaw who joins forces with Matt Dillon to track down a member of his former gang who has escaped jail.