An arid climate accompanied by a freshwater shortage plagued Egypt. It has resorted to groundwater reserves to meet the increasing water demands. Fossil aquifers were lately adopted as the sole water source to provide the irrigation water requirements of the ongoing reclamation activities in barren areas. Yet, the scarcity of measurements regarding the changes in the aquifers’ storage poses a great challenge to such sustainable resource management. In this context, the Gravity Recovery and Climate Experiment (GRACE) mission enables a novel consistent approach to deriving aquifers’ storage changes. In this study, the GRACE monthly solutions during the period 2003–2021 were utilized to estimate alterations in terrestrial water storage (TWS) throughout Egypt. Changes in groundwater storage (GWS) were inferred by subtracting soil water content, derived from the GLDAS-NOAH hydrological model, from the retrieved TWS. The secular trends in TWS and GWS were obtained using the linear least square method, while the non-parametric technique (Mann–Kendall’s tau) was applied to check the trend significance. The derived changes in GWS showed that all aquifers are undergoing a significant loss rate in their storage. The average depletion rate over the Sinai Peninsula was estimated at 0.64 ± 0.03 cm/year, while the depletion rate over the Nile delta aquifer was 0.32 ± 0.03 cm/year. During the investigated period (2003–2021), the extracted groundwater quantity from the Nubian aquifer in the Western Desert is estimated at nearly 7.25 km3. The storage loss from the Moghra aquifer has significantly increased from 32 Mm3/year (2003–2009) to 262 Mm3/year (2015–2021). This reflects the aquifer exposure for extensive water pumping to irrigate newly cultivated lands. The derived findings on the aquifers’ storage losses provide a vital source of information for the decision-makers to be employed for short- and long-term groundwater management.