The prehistoric settlement of Sesklo occupies an area of 100,000 square metres, which includes the hill of Kastraki and the surrounding plain, dubbed 'acropolis' and 'polis' by Tsountas. The region is criss-crossed by a network of seasonal streams, while the settlement itself is located between two streams, which have badly eroded the site. Remnants of the settlement are now visible on the hilltop (Sesklo A), on the plain to its west (Sesklo B) and in the area northeast of the hill (Sesklo C). They belong primarily to the Middle Neolithic (5800-5400 BC), when the settlement was at its peak, and consist of the stone foundations of small houses with the same orientation and narrow streets running between them. All houses have stone foundations, mud brick walls and wooden beam roofs covered with clay. When destroyed, they were re-built on the same spot. Inside they had hearths, small storage facilities and food preparation and living areas.

On the hill (Sesklo A), at the centre of the settlement, is a small 'megaron' of the Middle Neolithic (7-8-9) with paved porch and back yard. Next to this is the so-called House of the Potter (11-12) in which the clay coating of the walls is preserved to a good height and three cross-walls probably supported a wooden mezzanine. The largest of the remaining houses is the almost rectangular House 50, near the hill's northeast edge. The houses are surrounded by large enclosures, possibly for safety and privacy. In the Late Neolithic, the 'megaron' was partly overlain by a similar but larger structure (1-2-3-4-5-6), surrounded by circular stone enclosures. Several houses and graves of later periods (up to the Middle Bronze Age) also survive on the hill.

On the plain southwest of the hill (Sesklo B) the houses of the Middle Neolithic are detached from one another and more spacious, often with an adjacent service area or annexe. Several houses and graves in this area belong to the Middle Bronze Age.