Scott AFB is one of the oldest Air Force bases in service. It was established in 1917 as Scott Field, named for Corporal Frank S. Scott, the first enlisted man killed in a military airplane crash. Scott AFB is the only US military base named for an enlisted service member.

The first use of Scott Field was as a training facility for Curtiss JN-3D "Jenny" biplanes, as the US Army attempted to catch up to the military air services of the United Kingdom, France, and Germany, the US having just entered World War One. These Jennies were used for some of the earliest aeromedical evacuation in military history, and a later base mission for Scott AFB.

Scott Field was initially on leased land, but in 1919 the War Department bought Scott's land and assigned the field to the US Army Air Service, which assigned the base to the lighter-than-air branch, and 1921 saw the relocation of the Balloon and Airship School to Scott Field from Brooks Field, Texas. A great many facilities were built at Scott to support the lighter-than-air mission, and the airship hangar was the second largest in the use, after Lakehurst Field's airship hangar, one of the largest buildings in the world at that time. The lighter-than-air mission continued until 1937, when the Air Corps abruptly ended blimp and balloon operation, and Scott AAB was designated the intended headquarters of the Army Air Corps.

In 1937 the giant hangar, old wooden enlisted barracks and housing, administration buildings, and mooring mast were all demolished in preparation for this headquarters relocation. New administration buildings, in Colonial style, new family housing, new enlisted housing, and new hangars were constructed in 1938, all in preparation for the base's new mission, which never occurred. World War Two's looming presence prevented this transfer, and Scott was refocused on it's aeromedical evacuation and transport mission, and with the expanded space and housing the Army Air Corps technical school was transferred to the base, concentrated on communications, the "Best Radio Operators in the World!" The war saw the training of a large number of radio operators and training and operation of many medical transport units.

The Cold War called for ongoing technical support and continued medical airlift for the Air Force and Army. The international shifts of the Cold War and post-Cold War did lead to some changes in Scott's missions, mainly in the expansion of the transport mission, but overall Scott's role in the Air Force has been stable. Scott has expanded and modernized it's base facilities repeatedly, both to modernize and to upgrade planes, communication equipment and medical equipment. In the 1950s the base added even more housing, including Pagelow Apartments and additional family and bachelor quarters nearby. In recent decades Scott has added an air refuelling mission, but the central role of Scott as a transport and airlift hub continues.