Terrestrial climatic data reflect variable and often conflicting responses to the global cooling event at the Eocene-Oligocene transition (ca. 34 Ma). Stable isotopic compositions of the tooth enamel of large, water-dependent, herbivorous terrestrial mammals are investigated here to better understand the European continental climate during the late Eocene–early Oligocene. High δ18OPO4 and δ13C values reflect a semiarid climate and ecosystem in the late Eocene. In the west-southwest region of Europe, these conditions prevailed until at least 33 Ma, after which it became more humid. A similar change was recorded north of the Alpine thrust, but it occurred 2 m.y. earlier. The north and west-southwest regions show a significant offset in δ18OPO4 composition between 35 and 31 Ma, indicating the influence of different air trajectories with different moisture sources (Atlantic versus Tethys). This also marks the presence of an orographic height in central Europe from the latest Eocene. After 31 Ma, a large drop in δ18OPO4 is registered, explained by altitude-induced fractionation on meteoric water isotopic composition. The related paleoaltitude change is estimated to be 1200 m, and the uplift could have taken place along the Alpine-Dinaridic orogenic system.