Although recent assessments have quantified the impact of ambient PM_2.5 on public health in China, air quality managers would benefit from assessing specific differences in premature mortality and its responses to air quality improvement. Using PM_2.5 data simulated by an observation-fused air quality model and an integrated exposure-response model for the full range of PM_2.5, we determined the premature mortality attributable to ambient PM_2.5 across mainland China in 2016. Overall, the total number of PM_2.5-related deaths nationwide was 1.31 million, of which lung cancer, chronic obstructive pulmonary disease, ischemic heart disease, and stroke represented 0.13, 0.13, 0.42, and 0.62 million, respectively. Per capita PM_2.5-related mortality in China was 95 per 100,000 person-years, and that of elderly people aged ≥75 years (1166 deaths per 100,000) was much higher than that of young people aged 25–44 years (11 deaths per 100,000). Additionally, there were significant spatial differences in premature deaths, which mainly occurred in regions with high PM_2.5 levels or/and population density. Halving deaths across mainland China required an average of 63% reduction of PM_2.5 nationwide and a decrease by 73% in high concentration regions exceeding 70 μg/m³ and 19% in low concentration locales below 10 μg/m³. Moreover, reducing PM_2.5 to the WHO interim target I (IT-1) of 35 μg/m³ would only result in a 12.6% reduction in premature mortality, while a more exacting standard (reducing PM_2.5 to 10 μg/m³) would avoid 73.0% of mortality. In particular, there is a large potential for reducing the high PM_2.5-related mortality in heavily polluted locales. In conclusion, to further reduce premature mortality across mainland China, targets stricter than the IT-1 and tight policies to improve air quality and protect public health are necessary, especially for vulnerable groups such as the elderly and patients with cardio-cerebrovascular diseases, particularly in areas with high premature mortality.