Gravity Recovery and Climate Experiment (GRACE) data and outputs of land surface model were applied to estimate the groundwater storage changes over the Nile Delta Aquifer (NDA) in northern Egypt during the period 2003–2012. Monthly solutions of GRACE data were used to estimate the Terrestrial Water Storage variations (ΔTWS) over the aquifer. The non-groundwater contributions were estimated from land surface model outputs (CLM4.5). These contributions were subtracted from the ΔTWS to estimate groundwater storage variations (ΔGWS) over the aquifer. The average annual precipitation (AAP) rates were estimated from the Tropical Rainfall Measuring Mission (TRMM) data and used to identify the time periods. The results were evidenced by geochemical, isotopic, and hydrogeological data. The average precipitation data over the aquifer are 1.8, 1.4, and 1.6 km3/yr during periods I, II, and III, respectively. (2) The groundwater depletion rates over the aquifer were estimated at −0.07 ± 0.028, −0.029 ± 0.044, and − 0.19 ± 0.058 km3/yr during periods I, II, and III, respectively. (3) The slightly low depletion of the groundwater in the aquifer is apparently caused by the compensation from the recharge water and the saline water intrusion. The average natural recharge rates were estimated at +3.65 ± 0.35, +4.98 ± 0.47, and + 5.91 ± 0.59 km3/yr during periods I, II, and III, respectively. The integrated approach provides valuable information for better assessment of the groundwater resource variations of large groundwater reservoirs and for developing sustainable management programmes of these resources.