Columbus Air Force Base began in 1941, as part of a War Department effort to prepare for expected war overseas. The Mississippi location was the result of a concerted civilian effort to present an attractive military site. Six months before the Pearl Harbor attack, the US Army Air Corps had already begun pilot training at Columbus, then named Kaye Field, for a World War One flying ace. This immediately caused confusion with another military field, Key Field, Mississippi, and Kaye Field's name was changed to Columbus Army Flying School in March 1942. Columbus became a training site for transport and bomber pilots, who were then sent on to other bases for group combat training. Training load increased at Columbus, until a peak graduate rate of 195 per month was achieved. 7,412 trainees gained wings and commissions at Columbus in World War Two. Flying innovations developed at Columbus include full panel instrument, "blind" flying, and the creation of the Flying Evaluation Board to judge a pilot's proficiency.

After the war Columbus was inactivated until the Korean War. Hostilities with North Korea, and increasing Cold War tension created a demand for pilots, and the threat of widespread nuclear bombardment created a demand for dispersed base units. Columbus was reactivated and renamed Columbus Air Force Base, as a training center and one of many strategic bomber and bomber support bases. This mission continued through the 1960s and the Vietnam War. In 1969 SAC transferred the strategic bombing mission away from Columbus and retasked the base to its former mission of pilot training, a mission it continues to perform. About half of all Air Force pilots were trained in basic flying at Columbus Air Force Base.