AbstractThe population of Santiago, Chile, experiences air pollution above global health guidelines that is attributable in part to large anthropogenic emissions. This is compounded by geographic features and meteorological conditions that are prone to pollution accumulation as well as secondary pollution production. In recent years, there have been improvements in air quality; however, the future of air pollution in Santiago remains unclear due to its growing population and increased vehicle use. Mitigation efforts can be supported by characterizing sources of air pollution and estimating how changes in emissions could affect air quality in future years. In this study, we conduct simulations using a chemical transport model (GEOS‐Chem) and perform adjoint calculations to characterize the relationship between health impacts associated with exposure to PM_2.5, O₃, and NO₂ and anthropogenic emissions. We incorporate model updates in a new nested domain simulation over Central South America including local and regional anthropogenic emissions inventories for Chile. We estimate that 2,490 (1,360, 4,060) PM_2.5‐ and O₃‐related premature deaths and 5,350 (1,320, 11,330) NO₂‐related new pediatric asthma cases were associated with pollution exposure in Santiago in 2015 and that a majority of these health impacts were attributable to anthropogenic emissions. We identify emissions from transportation, energy generation, and residential combustion as the leading contributors to these health impacts. Additionally, we estimate that Chile's commitment to attain carbon neutrality by 2050 could result in benefits in Santiago of 3,230 (1,240, 7,160) avoided deaths and 2,590 (640, 5,500) avoided pediatric asthma cases in 2050 compared to business‐as‐usual emissions.