Vance AFB began construction in the summer of 1941, as part of an Air Corps expansion in the days immediately before the US entry into World War Two. Construction began with the arrival of the commanding officer and staff, and as the alternating muddy and dusty conditions on site made operations impossible, Major Henry Dodd set up headquarters in the nearby town of Enid until construction was finished enough to function. The leaders of Enid had specifically lobbied for their site to be selected for Army development, and arranged a very cheap land deal, plus a locally funded package of electrical and water improvements. Operations on site began in November 1941, less than a month before the US was drawn into the war.

At first this new airfield was nameless, only referred to as the Air Corps Basic Flying School at Enid. The school quickly got to work training aviation cadets into actual pilots, only one week after the attack on Pearl Harbor. Early training was complicated by ongoing red dust stirred up by construction, and cadets would generally return from a full day's training to clean their housing floors and windows from blown dirt.

The field was soon officially activated, with the training facility named the Enid Army Flying School, in March 1942. By the end of the war, Enid Army Air Field (as it was renamed in 1943) had graduated over eight thousand cadets from basic flight school, and over eight hundred from advanced flight school. The demand for pilots dropped at the end of World War Two, and the War Department inactivated Enid Army Air Field in January 1947.

Enid Air Force Base reactivated in August of 1948, as the newly separated Air Force wished to expand its pool of pilots in light of the rapidly developing Cold War. The new base's mission was to provide advanced pilot training for multiengine aircraft. Enid AFB was renamed Vance Air Force Base in 1949 to honor an Enid native, Medal of Honor recipient Lt. Col. Leon Robert Vance. Lt. Col. Vance had died in 1944, victim of a crash in transit between Iceland and Newfoundland, returning for medical treatment after his Medal of Honor earning actions, having successfully completed his bombing support mission during the Invasion of Normandy, despite being severely wounded.

The aircraft training mission continues at Vance, with some additions as a result of post-Cold War force realignments, notably undergraduate training, and assisting Naval Aviators in their training.