The Sierras Pampeanas of Argentina have been used as a classic case study to understand the processes and mechanisms involved in thick-skinned deformation; however, the history of exhumation and uplift of these ranges remains enigmatic. This study presents new thermochronology and field observations from the Sierra de Velasco, one of the highest relief (〉4 km) and least studied mountains in the Sierras Pampeanas. Advances in the annealing and diffusion kinetics of the apatite fission track and (U-Th-Sm)/He systems provide the tools to interpret a data set with a complex Carboniferous to Miocene cooling history. Our results show that rocks sampled across 2 km of structural depth have experienced protracted exposure to temperatures at or above ∼60 °C from ca. 320 to 120 Ma. The well-constrained thermal history allows us to identify subsequent thermal perturbations including an elevated geothermal gradient during Cretaceous rifting, late Cretaceous–Paleocene cooling due to isothermal relaxation and/or exhumation, and accelerated Miocene exhumation. Quantitative estimates of the minimum rock overburden suggest that 1.0 ± 0.8 km of rock has been eroded from the Sierra de Velasco since the early Miocene. Although a low geothermal gradient (≤25 °C/km) may support the exhumation of Sierra de Velasco coincident with the onset of flat-slab subduction in the late Miocene, we suggest inherited paleotopography existed before the Miocene and possibly since the Paleozoic. Final cooling and exhumation beginning in the early to middle Miocene, concurrent with the onset of flat slab subduction, contributed to the topography observed today, but cannot explain the entirety of the modern relief. We propose that a history of long-lived topography may be extrapolated throughout the Sierras Pampeanas region.