Environmental particulate pollution is a major global environmental health risk factor, which is associated with numerous adverse health outcomes, negatively impacting public health in many countries, including China. Despite the implementation of strict air quality management policies in China and a significant reduction in PM2.5 concentrations in recent years, the health burden caused by PM2.5 pollution has not decreased as expected. Therefore, a comprehensive analysis of the health burden caused by PM2.5 is necessary for more effective air quality management. This study makes an innovative contribution by integrating the Enhanced Vegetation Index (EVI), Normalized Difference Vegetation Index (NDVI), and Soil-Adjusted Vegetation Index (SAVI), providing a comprehensive framework to assess the health impacts of green space coverage, promoting healthy urban environments and sustainable development. Using Nanjing, China, as a case study, we constructed a health impact assessment system based on PM2.5 concentrations and quantitatively analyzed the spatiotemporal evolution of premature deaths caused by PM2.5 from 2000 to 2020. Using Multiscale Geographically Weighted Regression (MGWR), we explored the impact of greening improvement on premature deaths attributed to PM2.5 and proposed relevant sustainable governance strategies. The results showed that (1) premature deaths caused by PM2.5 in Nanjing could be divided into two stages: 2000–2015 and 2015–2020. During the second stage, deaths due to respiratory and cardiovascular diseases decreased by 3105 and 1714, respectively. (2) The spatial variation process was slow, with the overall evolution direction predominantly from the southeast to northwest, and the spatial distribution center gradually shifted southward. On a global scale, the Moran’s I index increased from 0.247251 and 0.240792 in 2000 to 0.472201 and 0.468193 in 2020. The hotspot analysis revealed that high–high correlations slowly gathered toward central Nanjing, while the proportion of cold spots increased. (3) The MGWR results indicated a significant negative correlation between changes in green spaces and PM2.5-related premature deaths, especially in densely vegetated areas. This study comprehensively considered the spatiotemporal changes in PM2.5-related premature deaths and examined the health benefits of green space improvement, providing valuable references for promoting healthy and sustainable urban environmental governance and air quality management.