This study delves into the sustainability of Groundwater Storage (GWS) in three major Middle East and North Africa (MENA) aquifers—the Nubian Sandstone Aquifer System (NSAS), North Western Sahara Aquifer System (NWSAS), and Murzuk Aquifer System—using Gravity Recovery and Climate Experiment (GRACE/GRACE-FO) and Global Land Data Assimilation System (GLDAS) data from January 2003 to December 2021. The NSAS, spanning multiple countries, experiences substantial GWS decline linked to reduced precipitation, rising temperatures, and increased evapotranspiration (ET). The NWSAS faces significant GWS depletion due to limited precipitation and elevated ET, highlighting hydrological challenges. In the Murzuk Aquifer, GWS exhibits a dual-stage decline exacerbated by changing climate conditions, declining precipitation, and equilibrium between precipitation and ET. These findings emphasize the MENA region’s need for proactive water resource management and climate change adaptation. For example, NSAS experiences alarming GWS depletion at − 1.28 ± 0.22 mm/year post-2009, while Chad sees positive GWS trends at 0.41 ± 0.04 mm/year due to higher annual precipitation. In the NWSAS, the substantial GWS depletion with a trend of − 3.62 ± 0.70 mm/year is attributed to low yearly mean precipitation of 84.48 ± 0.83 mm/year and high ET of 83.52 ± 0.97 mm/year. In the Murzuk Aquifer, GWS depletion sharply declines at − 2.41 ± 0.65 mm/year post-2010, emphasized by low annual precipitation of 30.12 ± 0.25 mm/year and elevated ET of 25.68 ± 0.33 mm/year. Despite relatively constant precipitation rates, there is a noticeable rise in groundwater depletion, indicating increased reliance on groundwater due to human activities in the MENA region.