Climate variability, population growth, and agricultural expansion increasingly strain groundwater resources in arid and hyper-arid regions. In West Mallawi, El-Minya Governorate, Egypt—where annual rainfall is less than 10 mm—the Middle Eocene and Oligocene–Pleistocene aquifers serve as the main sources of domestic and agricultural water. This study aims to support sustainable groundwater management by comparatively assessing their hydrochemical characteristics, water quality, and potential health risks. In 2024, 86 groundwater samples were collected and analyzed for physicochemical parameters, hydrochemical facies, and water quality indices. The deeper Middle Eocene aquifer exhibited higher total dissolved solids (TDS) and greater mineralization than the shallower Oligocene–Pleistocene aquifer. Hydrochemical facies analysis revealed predominant sulfate–chloride–sodium water types, influenced by evaporite dissolution, cation exchange, and prolonged water–rock interaction. Water Quality Index (WQI) evaluations indicated that most Oligocene–Pleistocene samples ranged from “good” to “poor,” whereas many Middle Eocene samples were classified as “poor” to “unsuitable” for drinking, with similar trends observed for irrigation suitability. Health risk assessment highlighted elevated hazard levels in the Middle Eocene aquifer, emphasizing the need for targeted treatment, routine monitoring, and strengthened groundwater management strategies. This comparative approach provides new insights into the vulnerabilities of aquifers under extreme arid conditions and offers evidence-based guidance for sustainable resource management.