Nitrate contamination of groundwater is a growing global concern, with severe health and environmental consequences, particularly in arid and semi-arid regions where groundwater is the primary water resource. This study investigates the extent and risk of nitrate pollution in the Southern Gabes aquifers, south-eastern Tunisia, addressing the research question: To what extent are these aquifers vulnerable to nitrate contamination, and what areas are most at risk? The conceptual framework integrates hydrogeological vulnerability assessment with spatial pollution risk modeling. Methodologically, the study employs the Intrinsic Vulnerability Index (IVI), Nitrate Pollution Index (NPI), Groundwater Nitrate Sensitivity Index (GNSI), and Groundwater Nitrate Pollution Risk Index (GNPRI), combined with geospatial analysis. The IVI indicates that 71.42% of the region faces moderate nitrate contamination risk, while only 0.36% shows negligible vulnerability, with 50 mg/L set as the critical drinking water threshold. Spatial correlation analyses reveal that areas of high nitrate concentration overlap with zones of intensive agricultural nitrate application. The integrated GNPRI highlights that 60.91% of the aquifer system has medium sensitivity to nitrate pollution, with 0.25% classified as highly sensitive. These findings not only identify priority zones for intervention but also provide an evidence-based framework for decision-making in groundwater protection. The implications of this research extend beyond regional boundaries, offering a transferable methodology for sustainable groundwater management in water-scarce environments worldwide.