Constraining the pre-Neogene history of the Puna plateau is crucial for establishing the initial conditions that attended the early stage evolution of the southern extent of the Andean plateau. We apply high- to low-temperature thermochronology data from plutonic rocks in northwestern Argentina to quantify the Paleozoic, Mesozoic and early Tertiary cooling history of the Andean crust. U-Pb crystallization ages of zircons indicate that pluton intrusion occurred during the early mid-Ordovician (490–470 Ma) and the late Jurassic (160–150 Ma). Lower-temperature cooling histories from40Ar/39Ar analyses of K-feldspar vary substantially. Basement rocks underlying the western Puna resided at temperatures below 200°C (<6 km depth) since the Devonian (∼400 Ma). In contrast, basement rocks underlying the southeastern Puna were hotter (∼200–300°C) throughout the Paleozoic and Jurassic and cooled to temperatures of <200°C by ∼120 Ma. The southeastern Puna basement records a rapid cooling phase coeval with active extension of the Cretaceous Salta rift at ∼160–100 Ma that we associate with tectonic faulting and lithospheric thinning. The northeastern Puna experienced protracted cooling until the late Cretaceous with temperatures <200°C during the Paleocene. Higher cooling rates between 78 and 55 Ma are associated with thermal subsidence during the postrift stage of the Salta rift and/or shortening-related flexural subsidence. Accelerated cooling and deformation during the Eocene was focused within a narrow zone along the eastern Puna/Eastern Cordillera transition that coincides with Paleozoic/Mesozoic structural and thermal boundaries. Our results constrain regional erosion-induced cooling throughout the Cenozoic to have been less than ∼150°C, which implies total Cenozoic denudation of <6–4 km.