The Puna-Altiplano plateau in South America is a high-elevation, low internal relief landform that is characterized by internal drainage and hyperaridity. Thermochronologic and sedimentologic observations from the Sierra de Calalaste region in the southwestern Puna plateau, Argentina, place new constraints on early plateau evolution by resolving the timing of uplift of mountain ranges that bound present-day basins and the filling pattern of these basins during late Eocene-Miocene time. Paleocurrent indicators, sedimentary provenance analyses, and apatite fission track thermochronology indicate that the original paleodrainage setting was disrupted by exhumation and uplift of the Sierra de Calalaste range between 24 and 29 Ma. This event was responsible for basin reorganization and the disruption of the regional fluvial system that has ultimately led to the formation of internal drainage conditions, which, in the Salar de Antofalla, were established not later than late Miocene. Upper Eocene-Oligocene sedimentary rocks flanking the range contain features that suggest an arid environment existed prior to and during its uplift. Provenance data indicate a common similar source located to the west for both the southern Puna and the Altiplano of Bolivia during the late Eocene-Oligocene with sporadic local sources. This suggests the existence of an extensive, longitudinally oriented foreland basin along the central Andes during this time.