Understanding climate and human impacts on water storage is critical for sustainable water-resources management. Here we assessed climate and human drivers of total water storage (TWS) variability from Gravity Recovery and Climate Experiment (GRACE) satellites compared with drought severity and irrigation water use in 14 major aquifers in the United States. Results show that long-term variability in TWS tracked by GRACE satellites is dominated by interannual variability in most of the 14 major US aquifers. Low TWS trends in the humid eastern U.S. are linked to low drought intensity. Although irrigation pumpage in the humid Mississippi Embayment aquifer exceeded that in the semi-arid California Central Valley, a surprising lack of TWS depletion in the Mississippi Embayment aquifer is attributed to extensive streamflow capture. Marked storage depletion in the semi-arid southwestern Central Valley and south-central High Plains totaled ∼90 km³, about three times greater than the capacity of Lake Mead, the largest U.S. reservoir. Depletion in the Central Valley was driven by long-term droughts (⩽5 yr) amplified by switching from mostly surface water to groundwater irrigation. Low or slightly rising TWS trends in the northwestern (Columbia and Snake Basins) US are attributed to dampening drought impacts by mostly surface water irrigation. GRACE satellite data highlight synergies between climate and irrigation, resulting in little impact on TWS in the humid east, amplified TWS depletion in the semi-arid southwest and southcentral US, and dampened TWS deletion in the northwest and north central US Sustainable groundwater management benefits from conjunctive use of surface water and groundwater, inefficient surface water irrigation promoting groundwater recharge, efficient groundwater irrigation minimizing depletion, and increasing managed aquifer recharge. This study has important implications for sustainable water development in many regions globally.