The station opened in 1915 as Royal Flying Corps Station Grantham, becoming RAF Station Grantham on 1 April 1918 - a name it bore until 1942 when it was renamed as RAF Station Spitalgate. Throughout the First World War the station was a flying training facility and headquarters of No. 21 Group RAF, RAF Flying Training Command. The main lodging unit was No. 12 Flying Training School RAF with further elements at the satellite station at RAF Harlaxton. Flying training continued at RAF Grantham during the inter-war years.
RAF Spitalgate should not be confused with HQ of No. 5 Group that was located in a large private house, St Vincents Hall, Grantham from October 1937 to November 1943 and also known as RAF Grantham during its final years there. Also in November 1943, elements of the HQ IX Troop Carrier Command of the United States Army Air Force were relocated to RAF Spitalgate, with their headquarters at St Vincents in the town centre. The station was also the training and point-of departure airfield for the Polish 1st Independent Parachute Brigade during Operation Market Garden.
The station was an Officer Cadet Training Unit (OCTU) in the 1950s. Much later it became the Women's Royal Air Force (WRAF) Depot, responsible for the recruitment and training of all non-commissioned females in the RAF, until this moved to RAF Hereford and later again to RAF Swinderby. It was also the home of the Central Gliding School which moved to RAF Syerston in March 1975. The site is not part of Grantham, but the parish of Londonthorpe & Harrowby Without.
Spitalgate acted as a parent station for a relief landing ground four miles further south at RAF Harlaxton from November 1916 until 1945.