The Panxi tectonic belt is located in the transition zone between the Tibetan Plateau and the Yangtze Block and is characterised by -N-S-trending faults and active earthquakes, which have long been considered to be a result of the growth (expansion and uplift) of the Tibetan Plateau. However, the mismatch between the -N-S-trending faults and top-to-the-SE arcuate thrust faults is problematic for understanding the mechanism of growth of the southeastern Tibetan Plateau. In this study, we integrate the results of structural analysis with new apatite fission track and (U-Th)/He thermochronological data to constrain the cooling, exhumation, and uplift history of the Panxi tectonic belt. Thermochronological data reveal that widespread and rapid cooling was initiated during the late Eocene-Oligocene (36-26 Ma), with a change in cooling/exhumation rate (either increase or decrease, dependent on location) occurring at 13-8 Ma (Middle-Late Miocene). These two periods of cooling are attributed to two major tectonic deformation episodes, D1 and D2. The D1 deformation is characterised by top-to-the-east/ southeast thrusting with back-thrusting along N-S-trending faults. The Middle-Late Miocene spatially differential exhumation was associated with D2 deformation involving strike-slip and local normal faulting that overprinted D1 and potentially accommodated accumulated strain. Integration of the new results with previous records of uplift and exhumation, sedimentation, magmatism, and fault activity, supports a diachronous staged uplift process of the southeastern Tibetan Plateau, with episodes during the late Eocene-Early Miocene and since the Middle-Late Miocene. Crustal deformation has played a significant role in promoting uplift through the generation of new faults and reactivation of pre-existing faults, whereas lower-crustal ductile channel flow might have driven the Middle-Late Miocene tectonic transformation in the upper crust.