Knox City, on State highways 6 and 22, Farm Road 143, and the Santa Fe Railroad, in a region known as Knox Prairie in southwest Knox County, was founded in anticipation of the arrival of the Kansas City, Mexico and Orient Railway, which began service in 1906. Originally the town was named Orient for the railroad. R. W. Warren and others donated land for a townsite, and Warren also built the first cotton gin in 1905. The town gained banks in 1905–06, a grain elevator before 1920, and other businesses, as well as a school and churches. It received electricity in 1916, natural gas in 1924, and city water and sewer service in 1922. The population was 1,127 in 1940, 1,488 in 1950, 1,805 in 1960, and 1,536 in 1970, when the town had fifty-five businesses. The state's first seed-testing plant started in Knox City in 1965. Fires did much damage before the public water supply was developed, particularly in 1911 and 1919. Worse yet was a tornado in March 1953 that struck the county hospital and other buildings. Losses included four deaths and damage to fifty homes. Knox City is a center for agribusiness and petroleum. The population was 1,546 in 1980 and 1,440 in 1990. By 2000 the population dropped to 1,219.