The story of the Archaeological Museum of Thessaloniki follows the course of history of the modern city of Thessaloniki. The Ephorate of Antiquities "under the General Directorate of Macedonia" was the first institution founded in November 1912, only two weeks after the signing of the treaty that handed over control of the city to Greece.

Construction at the Archaeological Museum of Thessaloniki began in 1960, on ΧΑΝΘ Square (YMCA) , in close proximity to the International Trade Fair grounds. The building was designed by the renowned architect Patroklos Karantinos, a prominent representative of the modernist movement in Greek architecture.

The Museum collections include numerous artefacts dating from the Prehistoric era to the end of antiquity. They come from excavations conducted throughout Macedonia since 1912, along with handed-in antiquities.