The airport was first established as an airfield during the First World War, as part of the allied war effort on the Macedonian front. There were numerous airfields at the time, including Little Mikra, Big Mikra (which became the current international airport), and the major military airfield of Sedes. The first international flight to Thessaloniki landed at the Little Mikra air field, and government efforts at encouraging the growth of civil aviation saw the start of construction of a purpose-built civilian airport at the present location in 1938. Works were temporarily abandoned due to the Second World War and the airport opened to civilian traffic in 1948.

Major works were undertaken after the war. The accession of Greece to North Atlantic Treaty Organisation saw NATO-funded investments such as the expansion of the 10/28 runway to 2,440 metres (8,010 ft) and the inauguration of a new terminal building in 1965. Damage to the tower caused by the 1978 Thessaloniki earthquake meant it needed to be torn down, and a new tower, still in operation, was built. Modernisation works were undertaken in the late 1990s, as part of the celebrations for Thessaloniki being European Capital of Culture in 1997. In 1993 the airport took the name Makedonia (Greek: Μακεδονία, Macedonia).

The operational aspects of the airport were privatised in 2015. Fraport AG/Copelouzos Group joint venture and the state privatisation fund agreed to the privatisation of the airport operations, and 13 other Greek airports, in December 2015. Fraport Greece will operate the airport for 40 years starting on 11 April 2017. It pledged to invest €400 million ($451.88 million) on the various airports, including a refurbishment of the existing facilities at Thessaloniki as well as the construction of a second terminal. Construction on the new terminal began on 19 September 2018 and finished in February 2021, three months ahead of schedule. Refurbishment works other than the terminal included the installation of an upgraded baggage handling system, the construction of three additional baggage reclaim belts, the connection of the wastewater treatment plant to the municipal service, the construction of a new airport fire station, and the construction of two new access control gatehouses to the previously unguarded apron. Fraport expects passenger traffic to increase by 48% by 2026 as a result of its investment.