Abstract: Reconstructing the thermal evolution of the eastern Qaidam Basin is important for gaining a deeper understanding of its lithospheric geodynamics and for more accurate hydrocarbon evaluation and prediction. This article presents a set of new apatite and zircon (U–Th)/He thermochronological ages. Combined with 336 vitrinite reflectance (Ro) data, the thermal history of the Ouanan Sag in the eastern Qaidam Basin has been reconstructed using inversion models. Three detrital samples from the Ounan Sag shows that the apatite (U–Th)/He ages are primarily concentrated in the range of 17.0 Ma to 76.5 Ma and that the zircon (U–Th)/He ages range from 200 Ma to 289.3 Ma. The time-temperature models demonstrate that the Ounan Sag experienced rapid subsidence and heating from the Carboniferous to late Permian, and exhumation/cooling events from the end of Permian to the Triassic. This thermal evolution was influenced by the widespread intrusion of plutons, and the collision and orogenesis caused by asthenosphere upwelling below the Qaidam arc, and slab rollback of the Southern Kunlun oceanic lithosphere, respectively. Additionally, our models depict the main exhumation/cooling stages since the Paleogene and a reheating event in the Miocene as a result of the intensifying growth of the Qinghai–Tibet Plateau and local sedimentary loading, followed by the initial India–Eurasia collision. Furthermore, the eastern Qaidam Basin experienced consistent heating during the late Paleozoic, reaching the maximum paleotemperature and geothermal gradient in the late Permian, with values of ∼230 °C and ∼43–44 °C/km, respectively. This study suggests that the source rocks in the most upper member of upper Carboniferous Keluke (C2k) Formations in the Ounan Sag reached the gas generation stage in the late Permian.