<p>This study examines the hydrogeochemical dynamics of the Katerini-Kolindros aquifer system in Central Macedonia, Greece, a vital freshwater resource for the local economy. Over a decade-long period (2010–2020), 751 groundwater samples from 113 wells were analyzed and the results processed using multivariate statistical techniques, hydrogeochemical mapping, and hierarchical cluster analysis. Four hydrogeochemical groups are delineated, revealing distinct influences of natural geological processes and anthropogenic activities. The dominant water types identified are Ca–HCO₃ and Mg-HCO₃, reflecting recharge conditions with no seawater intrusion, even in coastal wells. The chemistry of groundwater is also shown to be affected by ion exchange processes and to a lesser extent by reverse ion exchange processes. Urban practices, such as septic tank leakage, urban waste management and fertilizer usage, are identified as the primary sources of nitrate contamination in localized hotspots, particularly near residential and recreational areas. By correlating hydrogeochemical data with geological formations, this study provides novel insights into the spatial variability of groundwater chemistry and identifies areas requiring targeted management. Overall, the study underscores the importance of integrating long-term hydrogeochemical datasets with advanced statistical analyses to unravel complex aquifer dynamics. Practical implications include recommendations for improved monitoring networks, land-use planning, and contamination mitigation strategies. Future research should focus on the creation of a comprehensive network of dedicated observation wells – both for piezometric and hydrogeochemical monitoring – and numerical modeling to refine groundwater flow predictions. This work contributes to global discourse on sustainable groundwater management, offering a replicable methodology for similar Mediterranean and semi-arid regions.</p>