Apatite (U-Th)/He and fission track dating and tectono-thermal history modeling were used to reconstruct the Meso–Cenozoic tectonic evolution of the Huangling paleo-uplift in the Middle Yangtze Block, South China. The tectono-thermal evolution showed different tectonic exhumation/subsidence processes in the tectonic evolution of the foreland basin. The apatite (U-Th)/He ages ranged from 31.3 to 77.8 Ma, recording the thermal events of the Cenozoic Himalayan movement and indicating progressive exhumation extending from the southeast to the northwest. The thermal information of the Mesozoic Yanshan movement period was recorded by the apatite fission track age with a pooled age of 93.8 to 147 Ma. The exhumation of the Huangling paleo-uplift began in the Late Jurassic. The tectono-thermal evolution was characterized by a rapid uplift during 140–115 Ma, subsidence during 115–60 Ma, a rapid uplift during 40–30 Ma, and a slow uplift from 30 Ma to the present. The western Hunan–Hubei Depression was exhumed in the Middle Jurassic, and the tectono-thermal evolution was characterized by a rapid uplift during 160–135 Ma, a slow uplift during 135–50 Ma, a rapid uplift during 50–25 Ma, and a slow uplift from 25 Ma to the present. This Cenozoic exhumation was a response to the far field effect of the eastward growth of the Tibetan Plateau. The Cretaceous basins exposed in the surrounding areas of the Huangling paleo-uplift (Zigui basin, Yichang slope, and Huaguoping synclinorium) are foreland basins formed by the bi-directional compression of the Qinling–Dabie orogenic belt and the Xuefengshan intracontinental deformation system.