Knox City lies north of Abilene on Hwys 6 and 22, Farm Road 143, and the Santa Fe Railroad, in a region known as Knox Prairie in southwest Knox County. It was founded in anticipation of the arrival of the Kansas City, Mexico and Orient Railway, which began service in 1906.
Today Knox City is a center for agribusiness and petroleum; the state's first seed-testing plant started there in 1965.
The population was 1,546 in 1980 and 1,440 in 1990.