a b s t r a c tWe investigated the mechanism of epidemics with the impacts of climate change and socio-economic fluctuations in the Ming and Qing Dynasties in China (AD 1368e1901). Using long-term and highquality datasets, this study is the first quantitative research that verifies the 'climate change / economy / epidemics' mechanism in historical China by statistical methods that include correlation analysis, Granger causality analysis, ARX, and Poisson-ARX modeling. The analysis provides the evidences that climate change could only fundamentally lead to the epidemics spread and occurrence, but the depressed economic well-being is the direct trigger of epidemics spread and occurrence at the national and long term scale in historical China. Moreover, statistical modeling shows that economic well-being is more important than population pressure in the mechanism of epidemics. However, population pressure remains a key element in determining the social vulnerability of the epidemics occurrence under climate change. Notably, the findings not only support adaptation theories but also enhance our confidence to address climatic shocks if economic buffering capacity can be promoted steadily. The findings can be a basis for scientists and policymakers in addressing global and regional environmental changes.