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The intermittent presence of large Pleistocene lakes in the southwestern interior of North America, a region that is now a semi-arid desert, suggests repeated oscillations between profoundly different climatic conditions. The origin of these shifts is still unresolved due to inconsistencies in existing climate proxy data (for example, pollen, lake levels, and oxygen isotopes in speleothems). To resolve the inconsistencies in the water balance over the last 10 to 60 kyr, we use uranium isotopic variations in secondary soil minerals to quantify net infiltration and precipitation along a north-south transect in western North America. We show that winter infiltration increased by 30 to 100 percent, and precipitation by a lesser amount, in the valleys of the Great Basin and Mojave deserts between 60 and similar to 26 ka. This increase in infiltration and precipitation preceded the Last Glacial Maximum (LGM) and the timing of most lake highstands in the region by 5 to 10 kyr, respectively, suggesting a possible Last Precipitation Maximum (LPM) that coincided with a minimum in winter insolation. Subsequent decreases in infiltration and precipitation after the LGM can be reconciled with the timing of lake highstands if colder summer temperatures due to a minimum in summer insolation reduced lake evaporation. The soil records, combined with a range of proxy data, suggest that seasonal insolation is the long-term driver for large shifts in both precipitation and surface water variability in the region.