Vulnerability is one of the most important drivers of risk, and efforts in reducing vulnerability have been shown to be an essential strategy for disaster risk reduction (DRR). However, for those developing countries experiencing rapid urbanization, like China, poor understanding of the dynamics of vulnerability has hindered the achievement of DRR goals as set out in the Sendai Framework. Therefore, this study aims to investigate the spatiotemporal evolution of human and economic vulnerability for China from 2000 to 2020, and further explore the impacts of socio-economic development and disaster risk management on vulnerability. The results show an overall declining trend for disaster-related fatalities, but an increasing trend for direct economic losses. Significant regional and provincial disparities of vulnerability are observed: both human and economic vulnerability are highest in western China, modest in central China, and lowest in eastern China. Both human and economic vulnerability to natural disasters is steadily declining for the period 2000 to 2020. Social development and hazard risk management level are found to have significantly negative effects on human and economic vulnerability, while significant effect of economic growth is not detected in our analysis. Urbanization rate and education level are the most important factors in shaping both human and economic vulnerability. Expenditures of DRR, an indicators of risk management, is also found to be a significant determinator of vulnerability. Our findings are useful in informing effective national and regional DRR policy, and can also be generalized to other developing counties with situations similar to those of China.With respect to economic vulnerability—represented by direct economic losses per trillion GDP—the average value for China in last 21 years is 7.17 billion RMB. In terms of overall trends, the 5-year moving average of economic vulnerability decreased from 12.2 billion RMB to 4.2 billion RMB in the period 2000 to 2020, a decrease of 65.6%. Although significant declining trends are also observed for Western, Central and Eastern China, the levels of economic vulnerability in the three regions are quite different. Average economic vulnerabilities for Western, Central and Eastern China over the past two decades are 17.2, 9.1 and 3.4 billion RMB, respectively, which demonstrates that Western China is the most prone to economic damages, while Eastern China is least likely to be economically disrupted. This regional disparity is also consistent with the regional distributions of annual reported direct economic losses from 2000 to 2020. Regarding the overall trends of economic vulnerability for the three regions, the 5-year moving average of economic vulnerability for Western China decreased from 16.0 to 6.3 billion RMB, a decrease of 60.6%; that of Central China, from 22.8 to 7.2 billion RMB, a decline of 68.4%; and that of the Eastern China, from 6.1 to 2.1 billion RMB, a decline of 65.6%.