Nantes airport owes its origins to a military airfield, conceived in 1928 on part of the current site. In 1936/7, the Société Nationale de Constructions Aéronautiques de l'Ouest opened an aircraft factory adjacent to the airfield, initially building MB.210 bombers, followed by M.S.406 fighters and LeO 45 bombers. In 1939, the first paved runway was constructed, with a length of 900 m (2,953 ft).

During World War II, the airfield was briefly used as a British Royal Air Force airfield before being captured by German forces. Under occupation, the aircraft factory was closed, and the airfield was used by the Luftwaffe as an airfield to bomb targets in England. As a consequence, the airfield was hit by a damaging air raid on 4 July 1943, which also destroyed the adjoining aircraft factory.

After the war, the airfield was again put into service by the French Air Force. The aircraft factory was rebuilt, and has since built sections of the Vautour fighter and the Caravelle airliner, before becoming part of Airbus. In 1951, the first commercial operations started, with a new terminal built between 1954 and 1960 and runway extensions to cater for larger aircraft.

Nantes Atlantique is currently the largest airport in the west of France. There were plans to have it replaced by an Aéroport du Grand Ouest, situated 30 km (19 mi) to the north-west of Nantes in the commune of Notre-Dame-des-Landes. The €580 million project was approved in February 2008, with plans to open it in 2017. However, after a nearly 40-year-long controversy regarding the usefulness and impact of such an airport, the project was officially cancelled on 17 January 2018.

On 19 January 2019, a small 6-seater aircraft carrying Argentinian footballer Emiliano Sala left the airport for Cardiff, Wales. Both Sala and the pilot died when the plane crashed in the English Channel. Subsequent investigation showed that pilot David Ibbotson was not licensed to fly passengers on a commercial basis, nor for night flying, and that the aircraft was not airworthy.