In response to the requirements of five major US airlines, Douglas designed and built the large 52-passenger DC-4, which made its first flight on 7 June 1938. This type was not put into production; instead a smaller unpressurised development was ordered by American, Eastern and United Air Lines. This, too, bore the designation DC-4 and the original aeroplane became the DC-4E. The new aircraft flew on 14 February 1942, by which time the US was at war and all 24 DC-4A built were taken by the armed forces.

The DC-4 had a retractable nosewheel undercarriage and was powered by four 820-1,080kW Pratt & Whitney Twin Wasps. It was, for its time, an ideal long-range heavy logistic transport with a payload of up to 9,980kg. The military production version was the C-54. A total of 207 C-54A were built, followed by increased-capacity C-54B, similar C-54D with Pratt & Whitney R-2000-11 radials, C-54E with convertible cargo/passenger interiors, and C-54G with new engines. Nine hundred and fifty-two Skymasters were completed for the USAAF and 211 for the US Navy which designated them as R5D Skymasters.

Used in all theatres of war, none achieved a more impressive record than those operated by the USAAF's Air Transport Command. With this Command C-54 established the first regular transport service across the North Atlantic, averaging for a long period 20 double-crossings per day. One, the VC-54C-DO Sacred Cow, served as President Roosevelt's special aircraft and a C-54B-1-DO was used by Prime Minister Winston Churchill.

After the war Douglas built 79 civil DC-4-1009 and many of the military aircraft became available for airline operation - mostly with 44 seats but later with as many as 86. On 7 March 1946 American Airlines was first to introduce DC-4 on US domestic services, between New York and Los Angeles. However in October 1945 American Overseas Airlines had introduced DC-4 on North Atlantic services.