On sensing the oncoming World War II, and not wanting to join the infantry, he learned to fly at the Happy Bottom Riding Club in the Mojave Desert — adjacent to the USAF's Muroc Field, now Edwards Air Force Base. In exchange for flying lessons from pioneer aviatrix Pancho Barnes, he agreed to milk and look after her cattle.

On gaining his commercial pilot's license in six months, Kerkorian learned that the British Royal Air Force was ferrying Canadian built de Havilland Mosquitos over the north Atlantic to Scotland. The Mosquito's fuel tank carried enough fuel for 1,400 miles (2,300 km), while the trip directly was 2,200 miles (3,500 km). Rather than take the safer Montreal–Labrador–Greenland–Iceland–Scotland route (although, going further north could mean the wings icing, and the plane crashing); Kerkorian preferred the direct "Iceland Wave" route which blew the planes at jet-speed to Europe – but it wasn't constant, and could mean ditching. The fee was $1,000 per flight, but the statistics were that only one in four completed the journey.[9] In May 1944, Kerkorian and his Wing Commander J.D. Woolridge rode the wave and broke the old crossing record. Woolridge got to Scotland in six hours, 46 minutes; Kerkorian, in seven hours, nine minutes. In two and a half years with RAF Ferry Command, Kerkorian delivered 33 planes, logged thousands of hours, traveled to four continents and flew his first four-engine plane.

After the war, having saved most of his wages, Kerkorian spent $5,000 on a Cessna. He worked as a general aviation pilot, and made his first visit to Las Vegas in 1944. After spending much time in Las Vegas during the 1940s, Kerkorian quit gambling and in 1947 paid $60,000 for Trans International Airlines, which was a small air-charter service which flew gamblers from Los Angeles to Las Vegas. He then bid on some war surplus bombers, using money on loan from the Seagram family. Gasoline, and especially airplane fuel, was in short supply at the time, so he sold the fuel from the planes' tanks, paid off his loan – and still had the airplanes. He operated the airline until 1968 when he sold it for $104 million to the Transamerica Corporation.[10]