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Abstract Quaternary climate changes are driven in part by variations in the distribution and strength of insolation due to orbital parameters. Continental climate variability is well documented for the most recent glacial-interglacial cycles, yet few records extend further back in time. Such records are critically needed to comprehensively assess the entire spectrum of natural climate variability against the backdrop of anthropogenic warming. Here, we apply uranium isotope geochronology to calcite deposits to date groundwater-table changes in Devils Hole cave, Nevada. The deposits record multi-meter groundwater-table fluctuations over the last 750,000 years, reflecting the long-term evolution of hydroclimate in this presently arid region. During periods between glacial or interglacial extremes, the water table responded sensitively to variations in 65°N summer insolation, likely caused by the increasing extent of North American ice sheets during cold period, which steered moisture-laden trajectories towards the southwestern USA. These orbitally-driven hydroclimatic changes are superimposed on a tectonically-driven long-term decline in the regional groundwater table observed prior to 438,000 ± 14,000 years ago.