Aiming to investigate the health risk impact of PM2.5 pollution on a heavily populated province of China. The exposure response function was used to assess the health risk of PM2.5 pollution. Results shows that the total number of premature deaths and diseases related to PM2.5 pollution in Shandong might reach 159.8 thousand people based on the new WHO (2021) standards. The health effects of PM2.5 pollution were more severe in men than in women. Five of the 16 cities in Shandong had higher health risks caused by PM2.5 pollution, including LinYi, HeZe, JiNing, JiNan, and WeiFang. PM2.5 pollution resulted in nearly 7.4 billions dollars in healthy economic cost, which accounted for 0.57% of GDP in Shandong in 2021. HeZe, LiaoCheng, ZaoZhuang, and LinYi were the cities where the health economic loss was more than 1% of the local GDP, accounted for 1.30, 1.26, 1.08, and 1.04%. Although the more rigorous assessment criteria, the baseline concentration was lowered by 30 μg/m3 compared to our previous study, there was no significant increase in health risks and economic losses. China’s air quality improvement strategy may already be having a positive effect.