The old Archaeological Museum of Larissa was housed at the Yeni Mosque, in the centre of the city. The building presented many problems, the main one being lack of space. As a result, the rich findings from the wider area of Larissa could not be exhibited and adequately highlighted.

After years of turmoil and as the need of moving had become imperative, the hill of Mezourlo was selected as the most appropriate site for the new Museum.

Mezourlo is situated at the south outskirts of the city, above the ring road of Larissa. The 14 acre land of the Museum was gradually handed over by the Municipality of Larissa to the Ministry of Culture.

In 1984 a national architectural competition was held regarding the construction of the Museum and the study of the architect P. Fotiadis and his associates was selected and implemented.

The building was founded in 1996, while its construction was completed in 2006. In 2008, the administration of the Museum was taken over by the XV Ephorate of Prehistoric and Classical Antiquities and the 7th Ephorate of Byzantine Antiquities.

The two Ephorates were both housed in the new building in 2010. The old Archaeological Museum closed down in 2012 in order for the exhibits to be transported and conserved.

In 2014 the two Ephorates were joined together to form the Antiquities Ephorate of Larissa.

On 28 November 2015 the Museum opened its gates to the public, an event which signified a new era for the culture of Larissa and Thessaly.