Sioux Falls Regional Airport was built on its present site as an airfield in 1937. In early 1942, the city approached the Federal Government and later leased the airport and surrounding property to become the Sioux Falls Army Air Field. The major function of the base was the establishment of a radio operator training facility. Between 1942 and 1945, about 40,000 radio operators were trained in Sioux Falls. The base was also a logistical supply center and its grid of streets now make up an industrial area just south of the present day airport. In 1946 the airport and surrounding land was transferred back to the city and the South Dakota Air National Guard was established under the direction of future airport namesake Joe Foss. The Air National Guard Base portion of the airport is south and west of the commercial and general aviation areas, north of Russell Street, and has all the standard facilities of a small USAF installation except for family housing. The 114th's F-16C and F-16D aircraft are a frequent sight over the Sioux Falls area, conducting training flights and routine operations.

Mid-Continent Airlines established the airport's first airline flights around 1940; the airline's successor, Braniff, left the airport about 1967. Western Airlines arrived in 1955, North Central in 1957, and Ozark in 1962. By 1992, the airport had 28 daily flights from eight airlines.

In 2005, Sioux Falls Regional Airport became one of the first airports in the country to de-federalize its workforce. Covenant Aviation Security previously provided baggage and passenger screening under contract with the Transportation Security Administration under the Screening Partnership Program. Currently, the Trinity Technology Group provides security screening functions.