Ambient pollutants, particularly fine particulate matter (PM2.5) and ozone (O3), pose significant risks to both public health and economic development. In recent years, PM2.5 concentration in China has decreased significantly, whereas that of O3 has increased rapidly, leading to considerable health risks. In this study, a generalized additive model was employed to establish the relationship of PM2.5 and O3 exposure with non-accidental mortality across 17 districts and counties in Jilin Province, China, over 2015–2016. The health burden and economic losses attributable to PM2.5 and O3 were assessed using high-resolution satellite and population data. According to the results, per 10 µg/m3 increase in PM2.5 and O3 concentrations related to an overall relative risk (95% confidence interval) of 1.004 (1.001–1.007) and 1.009 (1.005–1.012), respectively. In general, the spatial distribution of mortality and economic losses was uneven. Throughout the study period, a total of 23,051.274 mortalities and 27,825.015 million Chinese Yuan (CNY) in economic losses were attributed to O3 exposure, which considerably surpassing the 5,450.716 mortalities and 6,553,780 million CNY in economic losses attributed to PM2.5 exposure. The O3-related health risks and economic losses increased by 3.75% and 9.3% from 2015 to 2016, while those linked to PM2.5 decreased by 23.33% and 18.7%. Sensitivity analysis results indicated that changes in pollutant concentrations were the major factors affecting mortality rather than baseline mortality and population.