Rapid economic development has led to massive fossil energy consumption and emissions of air pollutants such as PM2.5, which have severely impacted human health and the environment. By uncovering the primary regions and pivotal sectors of PM2.5-related human health impacts (PM2.5-HHI) and evaluating the influence of economic structural factors on them, we can facilitate a more targeted strategy for managing PM2.5 pollution sources. This study employs a structural decomposition analysis method based on input–output analysis to evaluate the impact of China’s provincial economic structural transformation and changes in final demand on PM2.5-HHI in the years 2012, 2015, and 2017. Results indicated that PM2.5-HHI is primarily concentrated in economically developed provinces (e.g., Shandong and Guangdong), which is compared to Shanghai, Heilongjiang, Liaoning, and Hebei experienced negative growth in PM2.5-HHI during 2007–2017. The production-based PM2.5-HHI is primarily driven by energy-intensive sectors such as the production and distribution of electric power and heat power. By contrast, the building sector is key to driving consumption-based PM2.5-HHI. An increasing number of regions are reducing PM2.5-HHI by implementing production structure changes. Moreover, the driving effect of production structure changes on PM2.5-HHI growth is strengthening in Beijing and Tianjin. Changes in the final demand structure mainly led to the growth of PM2.5-HHI in areas with higher economic development levels, such as Beijing and Shandong, but this driving effect is weakening. The final demand–driven PM2.5-HHI shows an evolutionary trend of an increasing share driven by fixed capital formation and exports and a decreasing share driven by household consumption. Changes in emission intensity play a key role in decreasing PM2.5-HHI in each region. Alternatively, changes in the structure of emission sources have a relatively minor impact on PM2.5-HHI. To mitigate PM2.5-HHI, regional economic and resource endowment advantages should be used to promote regional coordinated development and strengthen green production-process innovation in energy-intensive industries. Meanwhcile, it is necessary to optimize urban construction planning and improve the energy efficiency of buildings.