Recent global groundwater overpumping is threatening ecosystem stability and food security, particularly in arid basins. A solid investigation regarding the drivers of groundwater depletion is vital for groundwater restoration, hitherto, yet it remains largely unquantified. Here, a framework to quantify the contribution of natural forcing (NF) and anthropogenic perturbations (AP) to groundwater storage anomalies (GWSA) variability by separating the GWSA estimated by the Gravity Recovery and Climate Experiment (GRACE) satellite into natural- and human-induced GWSA was proposed in the northwest endorheic basin (NWEB) of China. Further, a multiple linear regression model was established for GWSA change prediction. Our results showed that, during the period 2003–2020, the GWSA depleted at a rate of 0.25 cm yr−1 in the entire NWEB. In addition, GWSA was found to decrease significantly (exceeding 1 cm yr−1) in the west of NWEB where there are heavily irrigated areas, and has become one of the regions with the most serious groundwater depletion in China. Whereas a significantly increasing trend (greater than 0.5 cm yr−1) was observed in the Qaidam basin and south part of the Tarim River basin, becoming a groundwater enrichment reservoir in NWEB. The negative contribution of AP to groundwater depletion has increased from 3% to 95% in the last decade, as determined by separating the effects of NF and AP on GWSA. The rapid expansion of the cropland area and the increase in water use due to population growth are investigated to be the main reasons for GWSA depletion, particularly in the North Tianshan Rivers, Turpan-Hami, and Tarim River basins. Therefore, we conclude that AP are dominating and accelerating groundwater depletion in the NWEB. The increase of GWSA in the Qaidam basin has been attributed to the increase in solid water melt and regional precipitation. The western route project of China’s south-north water diversion and water-saving irrigation are important ways to solve the problem of groundwater depletion in NWEB. Our results emphasize that a more feasible framework capable of reliably identifying the driving factors of groundwater storage change is a necessary tool for promoting the sustainable management of groundwater resources under both NF and AP in arid endorheic basins.
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