Gravity Recovery and Climate Experiment (GRACE) data with other data sets are used to estimate the mass variations over the Eastern Desert. These variations are caused by changes in terrestrial water storage (ΔTWS). Monthly GRACE and Mascon Solutions with other relevant data are conducted. Findings are (1) the Eastern Desert is witnessing a dry climatic period (April 2002 to July 2012) with lower average annual precipitation (AAP) rate of 9.3 mm and a wet climatic period (August 2012 to July 2016) with slightly higher precipitation rate of 14.1 mm; (2) the average trends in ΔTWS over the study area are estimated at − 4.40 ± 0.63 mm/year and + 4.37 ± 20.7 mm/year during the dry and wet periods, respectively; (3) the spatial distribution of the ΔTWS values during the wet period are consistent with the distribution of the rainfall, and the water leakage from Lake Nasser towards the surroundings though fault conduits; (4) the groundwater storage variation (ΔGWS) shows a negative trend of − 3.95 ± 0.63 mm/year during the dry period, while it shows a positive trend of + 4.98 ± 2.00 mm/year for the wet period; (5) Lake Nasser shows slightly higher water level variations during the wet period, in comparison to that of the dry period; (6) the surface water is draining eastward into the Red Sea and westward into the Nile River and partially feeding the underground aquifers through the permeable outcrops and/or along the sub-vertical deep-seated faults. Results provide new information on the mass variations of the Eastern Desert, caused by the change in the water storage in response to the climatic variation and global warming. The lowlands of the main valleys may represent the promising areas for agricultural development in the Eastern Desert.