During World War II, the United States Army Air Forces (USAAF) built John Payne Field Air Force Base to serve the Allied Forces, rather than take over the existing Almaza Airport located 5 kilometres (3.1 mi) away. Payne Field was a major Air Transport Command air cargo and passenger hub, connecting westwards through Benghazi Airport (during the war known as Soluch Airfield) to Algiers airport on the North African route to Dakar Airport, in French West Africa.

Other locations that transport routes were flown were RAF Habbaniya, Iraq on the Cairo – Karachi, India route; Lydda Airport, British Palestine; Jeddah, Arabia, on the Central African route to Roberts Field, Liberia (1941–1943), and later, after the war ended, Athens, Greece and on to destinations in Europe.

When American forces left the base at the end of the war, the Civil Aviation Authority took over the facility and began using it for international civil aviation. In 1963, Cairo International Airport replaced the old Heliopolis Airport, which had been located at the Hike-Step area in the east of Cairo.

The airport is administered by the Egyptian Holding Company for Airports and Air Navigation, which controls the Cairo Airport Company, the Egyptian Airports Company, National Air Navigation Services and Aviation Information Technology, and the Cairo Airport Authority. In 2004, Fraport AG won the management contract to run the airport for eight years, with options to extend the contract twice in one-year increments.