Based on the apatite fission-track dating evidence and modeled time-temperature thermal history, the MesozoicCenozoic tectonic-thermal evolution was quantitatively studied in the Zigui Basin. The results indicate that the uplift of the Zigui Basin began slowly around ~120 Ma and continued through three stages: (1) strong uplift during about 10080 Ma, resulting from the Yanshanian orogeny and Huangling anticline westward extension since the Late Cretaceous; (2) uplift during the late Eocene around 40 Ma, associated possibly with the collision between the Indochina block and Eurasian plate; and (3) strong uplift during the middle and late Miocene around 105 Ma, accompanied by the eastward growth of the Tibet Plateau and Asian monsoon climate change. Although there were continuing uplift and denudation since the Cretaceous in the internal Zigui Basin, they differed from the tectonic-thermal evolution at the basin margin. Comparing with the Dangyang Basin located in the east of Huangling, the results indicate that Huangling had exposed to the surface since Late Cretaceous which resulted in the separation of these two basins. During the Late JurassicEarly Cretaceous, large-scale extrusion deformation and thrust-nappe structure in the Qinling Mountains contributed to the relatively older ages of AFT in the Micang Mountains and Huangling anticline among the MiddleUpper Yangtze Block; while the JiangnanXuefeng orogeny extending to the northwest resulted in the younger ages of AFT as whole from western Hubei-Hunan to eastern Sichuan. Similarly, the subduction of the Pacific plate since the Late Cretaceous caused AFT ages younger from southeast to northwest in the eastern Sichuan fold belt and northeastern Sichuan; and the young AFT age in the Jianghan and Dangyang basins west of the Longquan Mountains resulted from the uplift of the Tibet Plateau, southeastward escaping extrusion and change of the Asian monsoon.