Originally known as "Maley", the town was founded in 1880 as a whistlestop on the Southern Pacific Railroad. It was renamed in honor of a visit by General Orlando B. Willcox in 1889. In the early 20th century, Willcox had the distinction of being a national leader in cattle production. Agriculture remains important to the local economy, but Interstate 10 has replaced the railroad as the major transportation link, and much of the economy is now tied to the highway, which runs immediately north of the town.
Willcox is the birthplace of Rex Allen, known as "The Arizona Cowboy", who wrote and recorded many songs, starred in several Westerns during the early 1950s and in the syndicated television series Frontier Doctor (1958–1959). Willcox was among the locations of 26 Men (1957–1959), another syndicated series that depicted true stories of the Arizona Rangers starring Tristram Coffin and Kelo Henderson.