During World War II, the Airport served multiple important functions such as a completion and modification center for the B-17 Flying Fortress, testing and training center for the modifications made to aircraft, and as a flight training center. Plains Airways operated 3 CPT schools for the Army Air Corps during WWII with headquarters at the Cheyenne Airport. Modifications to the gunning turrets and armament were made and calibrated in three facilities, one of which now houses the headquarters of the Wyoming Air National Guard.

Both the flight and ground operations for Plains Airways were managed by W. Dillard "Pic" Walker who was among the first inductees into the Wyoming Aviation Hall of Fame (located in the Airport's Terminal). Plains trained more than 5,000 pilots and mechanics for the war effort. Walker also established the Cheyenne Squadron of the Civil Air Patrol (CAP) as one of the founding members of the organization back in the 1940's (a Civil Air Patrol Uniform from that era is on display in the Terminal).

Ralph S. Johnson was responsible for the engineering and testing of the hundreds of B-17's, B-24's, and PBY's coming through the modification center. The "green" aircraft were flown from the factory into Cheyenne where they were modified with all the armaments and combat equipment, then test flown by Johnson and his crews. Once determined to be fit for flight, the aircraft were delivered to combat units, some based as far away as New Guinea and Australia. Johnson and his crews test flew some 10,000 airplanes during the war.