The Nestos River delta is one of the most important and sensitive basins in Greece and Europe due to its ecosystem functions, combining intensive agricultural production with low-enthalpy geothermal energy and important ecotopes. High water quality is of paramount importance to the sustainability of the system. Systematic and continuous assessment of water quality needs to be carried out in a way that is easy and quick for decision makers and non-expert societal partners to comprehend. In this way, decisions may be made more rapidly, and involved water users may be sensitized to rational water use. To this end, this paper presents the assessment of groundwater quality in the Nestos River’s western delta with the use of Poseidon (PoS), a versatile, index-based method. Groundwater samples collected from 24 and 22 wells tapping the unconfined and the confined aquifers, respectively, in four time periods (May and October 2019 and 2020) were analyzed. Using the PoS index, groundwater samples were classified according to their quality status, highlighting the parameters driving quality degradation issues, thus assisting water managers in obtaining an overview of quality status and evolution through datasets that were often large. PoS index is applied in the study area for the first time and provides a groundwater quality assessment through a unique score representative of the overall water quality status regardless of processes (anthropogenic or natural) or any kind of pressures.