We present a multidisciplinary study that constrains the development history of the southern part of the Central Andean Plateau, a prototypical noncollisional orogenic system. In the Antofagasta de la Sierra region of NW Argentina, data from sedimentary geology, sandstone modal composition, detrital zircon U-Pb geochronology, and apatite fission-track and (U-Th-Sm)/He thermochronology indicate that sediments accumulated in the late Eocene to early Oligocene, with a maximum depositional age of ca. 39–38 Ma provided by the youngest detrital zircon U-Pb dates. Provenance data, including paleocurrent indicators, sandstone modal composition, and detrital zircon U-Pb ages, point to prevailing western sources, including the Sierra de Quebrada Honda (a proximal source), the Ordovician to Late Cambrian Famatinian magmatic arc in western Argentina and Chile (a distal source), and the Permian–Triassic plutonic and volcanic rocks in coastal Chile (a distal source). Along the western basin margin, these strata were deformed by a basement-involved thrust fault that was active at ca. 25–20 Ma, as constrained by apatite fission-track and (U-Th-Sm)/He data. Analysis of new and existing U-Pb geochronologic data from both detrital and basement samples across the Puna suggests that the Sierra Laguna Blanca, a major mountain range in the southern Puna, remained buried during the late Eocene to early Oligocene. Our multidisciplinary data indicate that the southern Central Andean Plateau may have hosted a regional basin primarily formed by lithospheric flexure during the late Eocene to early Oligocene. Furthermore, this study refines the history of basin compartmentalization and exhumation of the major mountain ranges in the southern Puna, revealing propagation of deformation from the west to east, starting as early as the late Eocene and continuing to the mid-late Miocene.