Continued Africa-Eurasia convergence resulted in post.11 Ma surface uplift of the Central Anatolian Plateau (CAP) and the westward escape of the Anatolian microplate. Contemporaneously, a central Anatolian fluvio-lacustrine system developed that covered extensive parts of the rising CAP. Today, the semi-arid CAP interior.except for the Konya closed catchment.drains toward the Black Sea, the Mediterranean Sea, and the Persian Gulf. Lake connectivity and drainage patterns of the fluvio-lacustrine system in the evolving plateau region are, however, largely unknown. Here, we present sedimentological and stable isotopic (δ13C and δ18O) data (N = 665) from 13 well-dated lake sections covering the former fluvio-lacustrine depocenters of the southern CAP. Persistently (>1 m.y.) stable paleoenvironmental and hydrological conditions suggest that a lowrelief environment characterized the southern CAP during plateau uplift. Throughout the late Miocene, various open and closed lakes of the southern CAP drained into closed, terminal lakes within the plateau interior. Sedimentation east of the Tuz Golu fault ceased during the early Pliocene (ca. 126.96.36.199 Ma), when the eastern CAP became connected to marine base level as a result of river incision shortly after the switch from regional compression to extension. A final phase of lacustrine carbonate sedimentation characterizes most sampled basins, yet occurred asynchronously over the extent of the CAP. Therefore, the final episode of lacustrine sedimentation is unlikely to have been the result of a climatic event, consistent with the absence of a clear aridification trend in the lacustrine δ18O data. Rather, capping carbonates reflect the interplay of surface uplift and transition from inward-to outward-drained plateau regions and concomitant lake reorganization during the formation of the CAP and its margins.