Silicate weathering reactions remove carbon dioxide from the atmosphere and store it in carbonate minerals. During the high atmospheric carbon dioxide conditions of the Early Eocene Climatic Optimum, rates of chemical weathering, physical erosion and denudation in the western USA were equivalent to the highest recorded rates in the non-glacial Quaternary. During the chemical weathering of silicate minerals, atmospheric carbon dioxide is incorporated into carbonate minerals and buried. As the rate of silicate weathering is thought to increase in response to increasing atmospheric CO2 concentrations, this represents an important negative feedback mechanism1. Quaternary records of weathering reflect a narrow range of pCO2 (180–300 p.p.m.v.)2; therefore, the extent of this feedback has been difficult to predict for increasing concentrations of atmospheric CO2. However, high CO2 levels of up to 1,125 p.p.m.v. have been suggested for the Early Eocene Climatic Optimum (52 to 50 million years ago)3,4,5. Here, we combine 40Ar/39Ar ages6 and the measured volumes of river-derived sediments and sodium-bearing evaporites to determine rates of physical erosion and chemical weathering in the Green River Basin, western United State of America, during the Early Eocene Climatic Optimum7. We find physical erosion rates of 420±79 t km2 yr−1 and chemical weathering rates of 62.5±21.9 t km2 yr−1. The calculated denudation rates of 175±30 m Myr−1 rival the highest documented non-glacial Quaternary rates for crystalline bedrock8. We suggest that elevated atmospheric CO2 levels during the Early Eocene epoch led to enhanced silicate dissolution rates9, and thus to increased production of loose rock material and higher rates of physical weathering and denudation.