Resolving thermal histories in sedimentary basins is crucial for interpreting orogenic growth, basin burial, and tectonic processes during Cordilleran orogenesis. In the Magallanes–Austral Basin, Patagonian Andes, we integrate new (U-Th)/He thermochronology, vitrinite reflectance (%R_o), calcite-cement clumped isotope data and thermal history modelling to resolve the origin of the regionally extensive Paleogene unconformity (51°S–50°S). Thermal history modelling results require post-depositional heating of Palaeocene (Danian–Selandian) strata below the unconformity and suggest maximum burial temperatures of 87°C–101°C (55–52 Ma) and 89°C–92°C (18–16 Ma). For lower Eocene strata above the unconformity, Miocene burial temperatures (89°C–92°C) are consistent with calcite cement formation temperatures (~62°C–92°C) from carbonate clumped isotopes. Our results indicate that basin burial and heating between ca. 60 and 52 Ma were likely driven by shallowing of the subducting Farallon plate and enhanced plate coupling preceding arrival of the Farallon–Phoenix mid-ocean ridge. Subsequent basin inversion and cooling from ca. 52 to 44 Ma correspond with subduction of this mid-ocean ridge. Refined thermal models, constrained by expanded thermochronometric and organic maturation datasets, indicate that up to ~1.7–2.0 km of proximal foreland basin strata were removed during uplift and erosion across the Paleogene basin margin. A return to basin subsidence beginning ca. 44 Ma may reflect dynamic subsidence after passage of the mid-ocean ridge and renewed coupling between the fold-thrust belt and foreland basin system. Neogene thermal histories document continued subsidence, localized hot orogenic fluid flow along stratigraphic boundaries, followed by a final phase of basin inversion and cooling at ca. 18–16 Ma, which we attribute to regional uplift associated with Chile ridge subduction. Altogether, this study demonstrates that multiple thermal indices when analysed and modelled can provide clarity for tectonic and stratigraphic events that affect foreland basins.