Originally used as a night-landing ground, by 1918 five hangars had been built and the centre became a training station. With the end of World War I the airfield was cleared. 1934 saw RAF Upwood reactivated and expanded to deal with the increasing threat posed by Nazi Germany.

The new base became operational in February 1937, housing two flying units. These original squadrons were reassigned in 1939 and replaced by No.90 and No.35 Squadron. Neither squadron saw combat and they were merged as No.17 Training Unit. When this unit departed Upwood in 1943, the grassed runways were replaced with three concrete runways.

The base re-opened in October 1943 and between 1944 and 1945 was used by No.139 and No.156 Squadrons. Their Mosquitos and Lancasters saw action in Germany, dropping target indicators over Berlin and bombing Stuttgart. After the end of the war they delivered food to the starving people of Holland and returned repatriated former Prisoners of War. In addition to housing several bomber units during the 1940s and 1950s, some of which took part in the Suez crisis, RAF Upwood was used as a location in the Dirk Bogard film 'Appointment in London'.

In 1961 Upwood was transferred to RAF Strike Command and by 1981 the base was almost dormant. Control was passed to the United States Air Force and Upwood became a satellite base of RAF Alconbury, providing housing and support for personnel. In 1986 a multi-million dollar medical facility was opened, delivering outpatient services to American military members in the area. The end of the Cold War saw a phased rundown of RAF Alconbury. The site was acquired by Strawsons in 1999 and in 2005 the last USAF family moved out of the Upwood housing area.