The Tibetan Plateau geographically contains internal and external drainage areas based on the distributions of river flows and catchments. The internal and external drainage areas display similar high elevations, while their topographic reliefs are not comparable; the former shows a large low-relief surface, whereas the latter is characterized by relatively high relief. The eastern Lhasa terrane is a key tectonic component of the Tibetan Plateau. It is characterized by high topography and relief, but the thermal history of its basement remains relatively poorly constrained. In this study we report new apatite fission track data from the eastern part of the central Lhasa terrane to constrain the thermo-tectonic evolution of the external drainage area in the southern Tibetan Plateau. Twenty-one new AFT ages and associated thermal history models reveal that the basement underlying the external drainage area in southern Tibet experienced three main phases of rapid cooling in the Cenozoic. The Paleocene-early Eocene (~60–48 Ma) cooling was likely induced by crustal shortening and associated rock exhumation, due to accelerated northward subduction of the NeoTethys oceanic lithosphere. A subsequent cooling pulse lasted from the late Eocene to early Oligocene (~40–28 Ma), possibly due to the thickening and consequential erosion of the Lhasa lithosphere resulted from the continuous northward indentation of the India plate into Eurasia. The most recent rapid cooling event occurred in the middle Miocene-early Pliocene (~16–4 Ma), likely induced by accelerated incision of the Lhasa River and local thrust faulting. Our AFT ages and published low-temperature thermochronological data reveal that the external drainage area experienced younger cooling events compared with the internal drainage area, and that the associated differentiated topographic evolution initiated at ca. 30 Ma. The contributing factors for the formation of the high-relief topography mainly contain active surface uplift, fault activity, and the enhanced incision of the Yarlung River.