Given the arid climatic conditions and the frequent long dry episodes in southwestern Tunisia, the sustainability of agricultural activities in this region depends entirely on the presence of sufficient quantities of accessible groundwater of suitable quality for agriculture. Hence, preserving the agrosystems that cover more than 7% of the fertile area of this region, which are of huge socioeconomic value, requires a critical assessment of the groundwater available to these systems. In this context, the present study was performed to determine whether deep groundwater resources are suitable for irrigating more than 54,000 ha of the Nefzaoua Oasis in southern Tunisia. The calculated values of ionic indices (SAR: 3.83–23.6; TH: 17.39–147.65; PI: 35.57–74.81; PS: 5.–79.29) and quality indices (IWQI: 17.14–83.39; CWQI: 17.64–63.96) for these highly mineralized waters indicate that they are unsuitable for irrigation purposes. The risk of land degradation in the Nefzaoua Oasis due to the use of unsuitable irrigation water are being amplified by inappropriate agricultural practices (inefficient drainage and excessive irrigation), mismanagement (the utilization of traditional irrigation techniques, irregular water distribution, and uncontrolled expansion of irrigated lands and water exploitation), and the harsh natural conditions present. The combined impact of these natural and anthropogenic constraints on the local environment necessitates the implementation of a detailed management scheme that utilizes detailed and flexible planning of rehabilitation activities to preserve the ecological and economic value of the agrosystems in this region.