Altus AFB was established in World War Two as Altus Advanced Flying School in 1942, and renamed Altus Army Airfield in 1943. After the war, the airfield hosted scrap and out of service aircraft, until the Korean War and Cold War created the need for additional bases for the newly created US Air Force. Altus became a training base for transport aircraft. It soon expanded to Tactical Air Command and Strategic Air Command missions, serving as a base for possible deep strike missions into Soviet territory using state-of-the-art bomber jets.

The 1960s saw continued expansion of Altus' mission, with the establishment of short-lived Atlas intercontinental ballistic missile sites, and increased training facilities for strategic airlift and transport craft. These missions continued to the end of the Cold War.

The post-Cold War era saw a realignment of Altus' missions, and a concentration of units and missions to Altus. In the 21st Century, Altus continues a primary role as a training, operations, medical, maintenance, and maintenance base.