The renewable groundwater resources in Egypt are restricted close to the Nile River. In the study area, two major water bearings are near the Nile: The Quaternary and the Eocene aquifers. Remote sensing (ASTER DEM, Landsat-8, and Sentinal-1 InSAR images), geochemical modeling, and isotopic constraints (delta O-18 and delta H-2) were employed and integrated with the GIS framework for delineating the low saline and sustainable groundwater zones. Remote sensing data indicates intensive structure lineaments in the middle-eastward part, spatially congruent with subsurface features deduced from radar satellites, facilitating hydraulic connections with the Nile water. The soil moisture index, land surface temperature, and salinity index in irrigated areas, reveal a strong association between in situ electrical conductivity values and satellite-derived spectral indices. The higher groundwater salinity in the middle eastern region coincided with high lineament density zones, and higher temperature zones, leading to increased rock water interaction that leads to groundwater salinization. The isotopic composition of the Quaternary aquifer ranges between -1.30 parts per thousand and +5.53 parts per thousand for delta O-18, while delta H-2 ranges between -11.49 parts per thousand and +34.47 parts per thousand. In the Eocene aquifer, delta O-18 ranges between -0.46 and +3.45 parts per thousand, while the delta H-2 ranges between -3.16 parts per thousand and +23.50 parts per thousand, indicating subsurface recharge from the Nile water. The simulation of the mass transport geochemical NETPATH model revealed mixing ratios from the Nile water ranging from 3.4% to 93.7%. Based on the results, the area is classified into four classes, class (1) represents samples of high conduit with Nile water (<50% mixing), class (2) represents samples of moderate conduit with Nile water (10-50% mixing), class (3) represents samples of low conduit with Nile water (<1-10% mixing), class (4) represents samples of water-rock interaction. The findings would be of great importance for delineating sustainable zones of the Nile Valley aquifers.