The Ming Dynasty Mega-drought (MDMD) (1637-1643) occurred at the end of Ming Dynasty and is the severest drought event in China in the last millennium. This unprecedented drought contributed significantly to the collapse of the Ming Dynasty in 1644, casting profound impacts on Chinese history. Here, the physical mechanism for the MDMD is studied. Based on paleoclimate reconstructions, we hypothesize that this drought was initially triggered by a natural drought event starting in 1637, and was then intensified and extended by the tropical volcanic eruption at Mount Parker in 1641. This hypothesis is supported by the case study of the Community Earth System Model-Last Millennium Experiment archive as well as sensitivity experiments with volcanic forcing superimposed on natural drought events. The volcano-intensified drought was associated with a decreased land-ocean thermal contrast, a negative soil moisture response and a weakening and eastward retreating West Pacific Subtropical High. Plain Language Summary The collapse of Ming Dynasty at 1644, and in turn, the historical transition from Ming Dynasty to Qing Dynasty significantly changed the Chinese history into a long period of conservative policy. The collapse of Ming Dynasty at 1644 is contributed greatly by the Ming Dynasty Mega-drought (MDMD) (1637-1643). In this study, based on paleoclimate reconstructions and climate modelling, we show that the MDMD is triggered by a natural drought event, and is then intensified and extended by the strong volcanic eruption at Mt. Parker in 1641. This “superposition” mechanism of MDMD and the spatiotemporal characteristics of this drought is reproduced by our volcanic sensitivity experiments with volcanic forcing superimposed on natural drought events, and the results demonstrate that the explosion of Mt. Parker at the end of a natural drought event amplified and extended the drought for 3 years, generating the mega-drought. The volcano-prolonged drought is associated with the failure of EASM, which is directly caused by the decreasing of land-ocean thermal contrast after volcanic eruption, and indirectly influenced by negative soil moisture feedback as well as weakening and eastward retreating of West Pacific Subtropical High (WPSH).