The site of Nea Nikomideia is one of the oldest and most important Neolithic settlements in Northern Greece and the wider Balkan Peninsula, having been first occupied by early farmers at around 6500 cal. BC. Important archaeological excavations conducted in the 1960s suggested that the settlement was located close to an ancient coastline during the Neolithic. However, palaeoenvironmental change and landscape evolution in the vicinity of the site have seldom been considered in detail. Six cores from the western and central parts of the Thessaloniki Plain were therefore drilled in 2008 and subjected to palaeoenvironmental analyses, including sedimentology (LASER grain size and magnetic susceptibility measurements), chemical analysis (loss on ignition and carbonate content), stable isotopes analysis coupled with X-Ray diffraction measurements, molluscan faunal analysis and radiocarbon dating. The recognition of several important facies representing freshwater (lacustrine and fluvial) and brackish (lagoonal and marine-influenced) conditions have shed light on the environmental and landscape evolution of the western part of the Thessaloniki Plain and associated impacts on human occupation during the last 10,000 years. The general sequence proved in the cores indicates the predominance of lacustrine conditions during the early Holocene, with the occurrence of a marine transgression at c. 6000/5800 cal. B.C. This major palaeoenvironmental change corresponds with the 8.2 Ka event and is a likely cause for the desertion of Nea Nikomideia at that time. Subsequent regression of the shoreline to the east saw that the area around Nea Nikomideia returns to predominantly terrestrial conditions and the deposition of lacustrine and fluvial deposits.