Groundwater salinization and contamination by nitrates represent two major environmental threats that can deteriorate its quality and pose serious health problems in many regions worldwide. This study aims to investigate the groundwater quality and to evaluate its suitability for drinking and irrigation purposes in the agricultural plain of Sidi Smail (northwestern Tunisia) using statistical, modeling, and GIS tools. A total of 59 groundwater samples and four surface water samples were collected in the autumn transition (October 2021) and the dry summer season (August 2022) and analyzed for pH, electrical conductivity (EC), total dissolved solids (TDS), and major ion concentrations. The results indicated that the majority of the groundwater samples were brackish/saline with an average TDS value of 2.225 mg/L in the autumn and 2.381 mg/L in the summer. The little increase in TDS values of surface and groundwater in the last season was attributed to the increase of evaporative demand and the decrease of rainfall amount. The groundwater mineralization in the plain had a significant spatial variability. The highest TDS values and concentrations of major ions were recorded in the southern sector of the plain due to the dissolution of Triassic evaporites deposits, while the lowest values were observed in the northern part of the plain likely due to the groundwater dilution caused by the infiltration of rainfall and seepage of surface water through faults of Ypresian karstic formations. The WQI values of groundwater ranged from 45 to 281, classifying the samples into four categories. In the autumn, 3% of samples were excellent, 36% good, 47% poor, and 14% very poor. In the season, 37% of samples were good, 43% poor, and 20% very poor. The integration of geochemical tools, statistical analyses, the water quality index (WQI), and GIS-based mapping constitutes a robust and comprehensive framework for assessing factors influencing the seasonal and spatial variations in sub-humid to semi-arid regions subjected to intensive agricultural practices. The results of this study highlight the urgent global need for the rational and controlled use of fertilizers to safeguard groundwater resources from nitrate contamination.