Data from the Gravity Recovery and Climate Experiment (GRACE) and outputs of the CLM4.5 model were used to estimate recharge and depletion rates for large aquifers, investigate the connectivity of an aquifer's subbasins, and identify barriers and preferred pathways for groundwater flow within an aquifer system. The Nubian Sandstone Aquifer System and its subbasins (Dakhla, Northern Sudan Platform, and Kufra) in northeast Africa were used for demonstration purposes, and findings were tested and verified against geological, geophysical, remote sensing, geochronologic, and geochemical data. There are four major findings. (1) The average annual precipitation data over recharge areas in the southern Kufra section and the Northern Sudan Platform subbasin were estimated at 54.8 km 3 , and 32.8 km 3 , respectively, and knowing the annual extraction rates over these two areas (~0.40 ± 0.20 km 3 ), recharge rates were estimated at 0.78 ± 0.49 km 3 /yr and 1.44 ± 0.42 km 3 /yr, respectively. (2) GRACEderived groundwater depletion rates over the Dakhla subbasin and the Northern Kufra section were estimated at 4.44 ± 0.42 km 3 /yr and 0.48 ± 0.32 km 3 /yr, respectively. (3) The observed depletion in the southern parts of the Dakhla subbasin is apparently caused by the presence of the east-west-trending Uweinat-Aswan basement uplift, which impedes the south-to-north groundwater flow and hence reduces replenishment from recharge areas in the south. (4) A major northeast-southwest-trending shear zone (Pelusium shear system) is apparently providing a preferred groundwater flow pathway from the Kufra to the Dakhla subbasin. Our inte-grated approach provides a replicable and cost-effective model for better understanding of the hydrogeologic setting of large aquifers worldwide and for optimum management of these groundwater resources.