This study presents a comprehensive assessment of groundwater quality changes in the Harran Plain, one of Turkey’s largest agricultural regions and a core zone of the Southeastern Anatolia Project (GAP), encompassing approximately 1,500 km². The research primarily aims to evaluate the impacts of intensive agricultural activity, evolving land use, and irrigation practices on groundwater pollution. Electrical conductivity (EC) and nitrate (NO₃⁻) concentrations were selected as key indicators of water quality. Spatial distribution maps based on seasonal averages were generated for the years 2005 and 2015 using data collected from 24 observation wells across the plain and evaluated against international standards (the WHO and the EPA) for drinking and irrigation water. In 2005, several wells exhibited critically high contamination levels, with EC values reaching up to 8,235 µS/cm and NO₃⁻ concentrations exceeding 720 mg/L. By 2015, these values had significantly declined in most areas—down to 2,510 µS/cm for EC and 327 mg/L for NO₃⁻—except in W11 (Uğurlu) and W14 (Kızıldoruk), where elevated levels persisted. These improvements are attributed to the implementation of closed drainage systems, adoption of pressurized irrigation methods, improved fertilizer management, and the introduction of more balanced and sustainable cropping patterns. Concurrently, a major transformation in land use was observed, including a shift from traditional cotton and grain farming to high-value, low-water-demand crops. However, the expansion of residential and industrial zones in certain areas introduced new environmental pressures, with some wells recording increased NO₃⁻ levels. Uncontrolled land development and irregular irrigation practices were identified as contributing factors. Moreover, the conversion of pasture and fallow lands into cultivated areas appears to have altered the groundwater recharge regime, impacting overall water quality. These findings highlight the critical role of integrated water–land policy approaches for sustainable groundwater management in arid agroecosystems.