Land use and climate change always induce significant changes in various parameters of the hydrologic cycle (e.g., surface runoff, infiltration, evapotranspiration). The Wadi El-Assiuti downstream area in the Eastern Desert of Egypt is one of the most promising areas for development that is suffering from insufficient water availability and inadequate water quality for different purposes. The main goal of this research is to evaluate the changes in groundwater quality, land use, and climate in association with geology and flooding during three periods within the years 1997–2019 in the downstream portion of Wadi El-Assiuti in the Eastern Desert of Egypt, using spatiotemporal variation associated with groundwater hydrochemical analysis and GIS techniques. About 133 groundwater samples were collected to examine groundwater quality changes over time. Different groundwater quality indices were calculated, and the results show that TDS levels of groundwater in the study area ranged between 1080–2780 mg/L, 672–4564 mg/L, and 811–6084 mg/L, while SAR levels varied within 6.15–15.34, 1.83–28.87, and 1.43–30.57 for the years 1997, 2007, and 2019, respectively. Both RSBC and SSP values exhibited significantly increasing trends over time. KR values were within 1.36–4.06 in 1997, 0.58–14.09 in 2007, and 0.35–14.92 in 2019; MAR values were within 6.9–45.2 in 1997, 20.79–71.5 in 2007, and 17.71–75.81 in 2019; and PI values were within 60.16–83 in 1997, 45.56–101.03 in 2007, and 42.51–148.88 in 2019. Across the entire study area, ongoing land use changes increased from 1.1% in 1997 to 4.1% in 2019. Findings pointed to the significant contribution of the deep Nubian Sandstone Aquifer to the groundwater aquifer at Wadi El-Assiuti through fractures and deep faults. Given the climatic conditions from 1997–2019, these changes may have affected water quality in shallow aquifers, especially with increasing evaporation. Realizing the spatiotemporal variation of the aquifer recharge system, land use development, and climate change clearly would help in water resource management. This study revealed that flooding events, deep-seated geologic structures, and land use development associated with human activities have the highest impact on groundwater quality.