Terrestrial water isotope records preserve a history of hydrological cycling that is influenced by past climate and surface topography. δ18O and δD records from authigenic minerals of the western United States display a long-term increase during the Neogene in the vicinity of the Sierra Nevada and the central Rocky Mountains (Rockies), but a smaller increase or decrease in the northern Great Basin. Interpretations of these isotopic trends require quantitative estimates of the influence of climatic and environmental changes on δ18O and δD of soil water. Here we use a coupled atmosphere-land model with water-isotopologue tracking capabilities, ECHAM5-JSBACH-wiso, to simulate precipitation and δ18O responses to elevation-independent changes in Neogene geography, equator to pole temperature gradient (EPGRAD), grassland expansion, and tropical Pacific sea surface temperatures. Both precipitation and soil water δ18O (δ18Osw) respond strongly to Neogene strengthening of the EPGRAD, but weakly to other forcings. An increase in EPGRAD leads to significant drying and 18O enrichment (3‰–5‰) of soil water over the northern Sierra Nevada and central Rockies as a result of Hadley circulation strengthening and enhanced coastal subtropical subsidence. These large-scale circulation changes reduce inland moisture transport from the Pacific Ocean and Gulf of Mexico. Our simulated δ18Osw responses could explain 50%–100% of the proxy δ18O increases over the Sierra Nevada and central Rockies, suggesting that climate change rather than surface subsidence may have been the dominant climate signal in δ18O records in these regions. On the contrary, δ18O responses to climate changes are small in the Great Basin, indicating that the observed δ18O increase over this region was likely a direct response to surface subsidence with elevation losses of 1–1.5 km. Adding this elevation loss to current Great Basin elevations reveals the former existence of a uniformly high plateau extending from the Sierra Nevada to the central Rockies prior to Neogene extension. This revised elevation history brings Neogene δ18O and δD paleoaltimetry of the western United States in accordance with independent lines of structural evidence and early Cenozoic elevation reconstructions.