Groundwater is considered a major and important source of water for drinking, agriculture, and industry. Groundwater management and monitoring is a great challenge for policy makers. Therefore, the main objective of this work was to emphasize the problem of accessibility to drinking water in the Siliana region, Tunisia, through groundwater prospecting and the identification of groundwater potential zones (GWPZs). A multidisciplinary approach based on several datasets and techniques such as remote sensing, multi-criteria analysis, and a spatially referenced hydrogeological information system was adopted. Eight thematic layers (geomorphology, slope, lineament density, drainage density, land use/land cover, precipitation, lithology, and soil) with significant effects on groundwater availability were integrated into our analysis. Weights were assigned to each parameter through an analytic hierarchy process (AHP)-based pairwise comparison matrix. The results indicated that the majority of the area shows significant groundwater potential. The results obtained showed that 0.45% of the study area has low potential, 70.30% has medium potential, and 29.34% has high potential. The validation of the results was conducted by initially comparing them with the locations of existing wells and boreholes and then by linking them with maps representing flow rates and transmissivities of water boreholes. Studying the locations of boreholes and wells in the study area, we found that the majority of the drilled wells are situated in high GWPZs, indicating significant potential for water storage. This finding is correlated by the wells identified in the study area. In fact, out of the total of 93 perennial wells in the present study area, 61.29% were found to be in high GWPZs, 36.56% were in medium GWPZs, and 2.15% were in low GWPZs. Overlaying the flow rate map with the GWP map indicated that 87.5% of the medium-flow drilling is located in high-GWP zones. Drilling carried out between the interception zones of medium and strong GWP shows a maximum flow of 115 l/s. Overlaying the transmissivity map with the GWP map indicated that high transmissivity is present in high-GWP zones. A comprehensive sensitivity analysis of a GIS-based Multi-Criteria Decision Making (MCDM) model was conducted to evaluate the criteria and their impact on the final model outputs. The lineament density factor was identified as the most important factor in the AHP model. This finding could help local decision makers to implement sustainable strategies for groundwater management.