Abstract: The epidemic diseases occurred in Nanjing during the Ming and Qing dynasties in 82 years, concentrated in the Chongzhen year, Jiajing year, and Wanli year of the Ming dynasty, as well as the Guangxu year, Qianlong year, and Daoguang year of the Qing dynasty. The epidemic usually occurred in summer in the Ming dynasty. However, in the Qing dynasty, it usually occurred in summer and autumn, mainly in a single season. The epidemic was mostly concentrated in Shangjiang County, and the epidemic was most widespread in the third year of Jiajing in the Ming dynasty (1524) and the nineteenth year of Guangxu in the Qing dynasty (1893). The most frequent epidemic in Nanjing in the late Qing dynasty was cholera, followed by malaria and dysentery. The main factors affecting the occurrence and prevalence of epidemics in Nanjing in the Ming and Qing dynasties were climatic anomalies, drought, famine, floods, earthquakes, and war. It is suggested that in improving the epidemic prevention system for public health, attention must be paid to protecting and improving the ecological environment.