One of the most pronounced climate transitions in Earth’s history occurred at the Eocene-Oligocene transition,∼ 34.0–33.6 my ago. Marine sedimentary records indicate a dramatic decline in pCO 2 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 (Δ 47)], δ 13 C and δ 18 O values of vadose carbonates, and δ 13 C values of bulk organic matter (δ 13 C org) in eastern Wyoming. Our results show that T (Δ 47) dropped from∼ 28 C to∼ 21 C, indicating∼ 7 C cooling in air temperature, which occurred parallel to the decrease in atmospheric pCO 2 during the latest Eocene–early Oligocene. We find that aridity and the biome were stable, and ice-volume–corrected precipitation δ 18 O 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.