One of the most pronounced climate transitions in Earth’s history occurred at the Eocene-Oligocene transition, ∼34.0–33.6 m.y. ago. Marine sedimentary records indicate a dramatic decline in pCO2 coeval with global cooling during the transition. However, terrestrial records are relatively sparse, with conflicting interpretations of hydroclimate in continental interiors. Here, we provide quantitative constraints on the response of the continental hydroclimate in the western United States across the Eocene-Oligocene boundary by studying clumped isotope temperatures [T(Δ47)], δ13C and δ18O values of vadose carbonates, and δ13C values of bulk organic matter (δ13Corg) in eastern Wyoming. Our results show that T(Δ47) dropped from ∼28 °C to ∼21 °C, indicating ∼7 °C cooling in air temperature, which occurred parallel to the decrease in atmospheric pCO2 during the latest Eocene–early Oligocene. We find that aridity and the biome were stable, and ice-volume–corrected precipitation δ18O decreased ∼1.6‰ across the Eocene-Oligocene boundary, attributable to reduced vapor condensation temperatures. These new quantitative data add to the growing body of evidence suggesting a marked terrestrial response in temperature and hydroclimate across the Eocene-Oligocene transition. Our findings indicate a pattern of greenhouse-gas–induced global temperature change in the continental interior of the United States that was roughly 1.5–2× the magnitude of cooling in the global ocean.