The airport was previously a Royal Air Force base, RAF Kirmington, opened in 1941 during the Second World War, from which No. 166 Squadron RAF operated the Avro Lancaster. The airfield was closed after the war in 1945, and lay unused as an airfield until 1973 when the local council decided to establish an airport at the site. Work included resurfacing the runways, installing lighting, construction of a new designated terminal building and the building of a taxiway. In 1974, construction finished and the site re-opened as Kirmington Airport. The first commercial flight took place in 1975 to Amsterdam. When the local area was renamed Humberside following local government re-organisation in England, the name was changed to Humberside Airport.

The main runway, designated 03/21 (since redesignated 02/20) was extended to its current length in 1992, allowing operation of much larger aircraft. In the 1990s, the Concorde landed and took off at the airport on several occasions.

In 2008, MAG, the owners at that time, announced that it was conducting a review of its strategy for Humberside Airport, and all options including disposal were under consideration. Initially it announced plans to sell Humberside Airport after nine years of ownership. In December 2008, MAG announced it intended to retain Humberside Airport, due to a number of investments, such as the new £1.6 million perishables hub, coupled with a surge in passenger numbers and little interest from potential bidders. MAG sold its 83.7% share of Humberside in 2012 for £2.3 million to Eastern Group to focus on the larger airports in its portfolio. It was later revealed that MAG had bought the airport for almost £8 million more in 1999.

Bristow Helicopters sold Eastern Airways in 2019, but retained its majority share of Humberside Airport.