Abstract: A large number of mass-death events in the Yangtze-Huaihe River Basin in the Ming Dynasty (1368—1644) were extracted from historical documents; a 10a-scale sequence of event frequencies, counties and breadths was constructed; the characteristics of time and space and hazard factors of the large number of death events were restored; and the coupling relationship between events and climate was analyzed. The results show that: ① There happened a total of 847 mass-death events in the Yangtze-Huaihe River Basin in the Ming Dynasty. Natural disasters, such as droughts, epidemics, floods and tides, were the main factors causing the mass deaths of the population. ② Mass-death events of the population showed significant phased and intermittent outbreak characteristics, with a cycle of fewer-more-fewer-more. ③ Spatially, a large number of deaths of the population were concentrated in the Yangtze River Delta, showing a ladder-like distribution. ④ Single factors accounted for the largest proportion (83.8%) of the disaster-causing factors of the mass-death events, among which droughts, floods, tides, epidemics and wars were the main ones. Regression analysis shows that there was a significant negative correlation between climate coldness and warmth and mass-death events. Cold and warm climate could explain 25.4%−35.1% of the large number of deaths. Meanwhile, dry and wet climate also had a significant negative correlation with mass-death events. Dry and wet climate could explain 10.5%−12.6% of the mass deaths of the population. Therefore, it can be said that climate change in the Ming Dynasty played an important role in the mass-death events, which further aggravated the mass-death events in the Yangtze-Huaihe Basin.