Quantifying the relationship between carbon cycle perturbations and the hydrologic cycle in the geologic past is crucial to accurately modeling how future anthropogenic carbon emissions and resulting radiative forcing might affect the hydrologic cycle. Interpreting changes in proxy records for insight into paleohydrologic change is complex, and documented records of paleohydrologic response to past global warming are rare. We use the relationship between two independent proxy records, the stable isotope ratios of hydrogen in n-alkanes and oxygen in tooth enamel of Coryphodon, to examine paleohydrologic change in the continental interior of North America during the Paleocene-Eocene Thermal Maximum (PETM) hyperthermal ~ 56 Ma. The Coryphodon δ18O record allows us to infer shifts in surface water isotope values through time by applying an empirical relationship between tooth enamel and precipitation δ18O values. Precipitation δ18O values increase by ~ 4‰ during the PETM, but n-alkane hydrogen isotope ratios show no directional change during the PETM. We explore multiple hypotheses that could explain the differences between the isotope records, including a change in apparent fractionation as a result of plant community change, a shift in the slope of the local meteoric water line, a change in the season of rainfall, or a shift in the season of lipid production. We model the changes that would be required to reconcile the isotope records for each hypothesis and evaluate the likelihood of each of the scenarios. We posit that the most likely hypothesis for the observed differences between the isotope records is a change in either the season of rainfall or the season of lipid production during the PETM.