Plate subduction leads to complex exhumation processes on continents. The Huangling Massif lies at the northern margin of the South China Block. Whether the Huangling Massif was exhumed as a watershed of the middle reaches of the Paleo-Yangtze River during the Mesozoic remains under debate. We examined the exhumation history of the Huangling Massif based on six granite bedrock samples, using apatite fission track (AFT) and apatite and zircon (U-Th)/He (AHe and ZHe) thermochronology. These samples yielded ages of 157–132 Ma (ZHe), 119–106 Ma (AFT), and 114–72 Ma (AHe), respectively. Thermal modeling revealed that three phases of rapid cooling occurred during the Late Jurassic–Early Cretaceous, late Early Cretaceous, and Late Cretaceous. These exhumation processes led to the high topographic relief responsible for the emergence of the Huangling Massif. The integrated of our new data with published sedimentological records suggests that the Huangling Massif might have been the watershed of the middle reaches of the Paleo-Yangtze River since the Cretaceous. At that time, the rivers flowed westward into the Sichuan Basin and eastward into the Jianghan Basin. The subduction of the Pacific Plate beneath the Asian continent in the Mesozoic deeply influenced the geomorphic evolution of the South China Block.