Understanding climate and human impacts on water storage is critical for sustainable water-resources management. Here we assessed causes of total water storage (TWS) variability from GRACE satellites by comparison with climate forcing, particularly droughts and irrigation water use, in major aquifers in the U.S.. Results show that long-term variability in TWS from 2002 – 2020 tracked by GRACE satellites is dominated by interannual variability in most of the major 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 semiarid California Central Valley, a surprising lack of TWS depletion in Mississippi is attributed to streamflow capture. Marked depletion in the 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 years) amplified by increased groundwater irrigation. Low or slightly rising TWS trends in the northwestern (Columbia and Snake Basins) U.S. are attributed to dampening of 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, amplifyied TWS depletion in the semiarid southwest and southcentral U.S., and dampened TWS depletion in the northwest and north central U.S.. 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.