Built during 1933-34 as the first of the new RAF bomber aerodromes in East Anglia, Mildenhall opened with a grass airfield and two Type A hangars in October 1934. It operated primarily as an RAF medium and heavy bomber base from 1934 to 1950, when it was allocated to Strategic Air Command (SAC) of the USAF. During the Second World War it controlled two satellite stations, RAF Newmarket Heath and RAF Lakenheath.



During the late 1930s to late 1940s, a hard-surface perimeter track plus a total of 36 aircraft dispersal points were laid, and three Class A intersecting concrete runways were laid and extended. Three Type C and two T2 hangers were added. From 1950, about a dozen B-50 Superfortress SAC bomb wings used the station on Temporary Duty (TDY) deployments, until Mildenhall became the main UK terminal for Military Airlift Command in 1958. The HQ of the 3rd Air Force moved to Mildenhall in 1962, and a tactical airlift wing was established there in 1963, to host Lockheed C-130 Hercules transports on TDY rotations from the USA. TDY rotations by SAC tanker squadrons led to a permanent Lockheed KC-135 unit at Mildenhall, which became the 100th Air Refuelling Wing in 1992. During the 1960s to 1990s, the main runway was further extended to 3,090 yards, and the base was enlarged to cover more than 1,200 acres, with accommodation for some 3,000 personnel. In 2015, the resident flying units are the 100th Air Refueling Wing, 501st Combat Support Wing, 352nd Special Operations Group, 95th Reconnaissance Squadron, 488th Intelligence Squadron and 727th Air Mobility Squadron.



It was announced in January 2015 by the US Department of Defense that RAF Mildenhall will close as a USAFE base after 2020. RAF Alconbury and RAF Molesworth will also close as USAFE bases in 2022. Roughly 2,600 personnel from Mildenhall are projected to be relocated to other bases in the UK and Germany. About 1,200 will move to RAF Lakenheath, which will be from 2020 the first and only USAFE base in Europe operating new Lockheed Martin F-35 Lightning II Joint Strike Fighters.