PM2.5 is one of the major pollutants in China and poses threats to human health. To better estimate the health burden caused by long-term PM2.5 exposure, we use PM2.5 data from high-resolution TAP (Tracking Air Pollution in China) database and CMIP6 (Coupled Model Intercomparison Project Phase 6) models to quantify premature mortalities attributed to PM2.5 pollution in China during the historical (2001–2019) and future (2030, 2045 and 2060) periods. Sensitivity experiments are also designed to explore the respective impacts of baseline mortality, population size, age structure, and PM2.5 concentration on health burden. Results show that population-weighted PM2.5 concentration in China over the last 19 years is 57.5 μg m−3, significantly higher than the unweighted value of 33.4 μg m−3. The national average premature mortalities attributable to long-term exposure to PM2.5 during 2001–2019 are 2363 (95%CI: 1991–2712) thousand, with severe health damage over Central China (454 (95%CI: 384–519) thousand), North China Plain (442 (95%CI: 375–503) thousand), and Yangtze River Delta (406 (95%CI: 343–465) thousand). The significant increase in premature mortalities in China during 2001–2005 (+213 thousand yr−1) is attributed to the growth in population size and the exacerbation of PM2.5 pollution, while the decrease in premature mortalities during 2013–2019 (−59 thousand yr−1) is primarily owing to the improvement in PM2.5 air quality. Future improvements in medical care and decreases in PM2.5 concentrations will help to alleviate the health burden in China. However, compared to 2019, national premature mortalities are projected to increase, especially during 2030–2060 with significant trends of +116∼+181 thousand yr−1 under different scenarios. The severe aging population in the future is the primary factor contributing to the increased health risks. In conclusion, severe PM2.5 pollution in China during the last 19 years has resulted in a large number of premature deaths, which will be further aggravated by population aging in the future. Therefore, it is imperative to implement more stringent air quality control measures to mitigate future health hazards associated with PM2.5 pollution.