The installation began as an aerodrome that was constructed in southeastern Sicily, at the foot of the Hyblaean Mountains ("Monti iblei") and near the city of Comiso.

Ground assault forces of the II Corps, under the command of (then) Lieutenant General Omar Bradley, captured the base on 11 July 1943.

During the Cold War, on 7 August 1981, it was officially selected as the second European main operating base for BGM-109G Ground Launched Cruise Missiles (GLCM), deployed by the North Atlantic Treaty Organization in response to the development and deployment of new intercontinental and intermediate range missiles by the Soviet Union.

On 17 March 1982, Commander George W. Holland, of the U.S. Navy Civil Engineering Corps, arrived at Comiso as the resident officer in charge of construction (ROICC).

A few of the old buildings were refurbished and used by the USAF or the Italian Air Force, but most were demolished carefully, because of the large amount of Second World War unexploded ordnance, a new base was constructed from the ground up, which was completed on 13 August 1982.

The 487th Combat Support Group was assigned to Comiso Air Station in May 1983; their efforts led to the 30 June 1983 activation of the 487th Tactical Missile Wing.

After these three demonstrations, which also involved a large number of Italian police, both local and national, the protesters appeared to lose interest and only a few very small incidents took place over the following years.

An ILS (Instrument Landing System) was installed and a new control tower 19 m (62 ft) high was built.

The first civil flight was made on a 30 April 2007, after the necessary tests and the inauguration of the new runway, but the airport was open to the traffic only on 30 May 2013.

A considerable proportion of the air traffic destined for Catania was diverted to Comiso, including flights from non-Schengen countries.