Background: PM2.5 pollution has been a persistent problem in South Korea, with concentrations consistently exceeding World Health Organization (WHO) guidelines. The aging of the population in the country further exacerbates the health impacts of PM2.5 since older adults are more susceptible to the adverse effects of air pollution. Objectives: This study aims to evaluate how the health impact (premature death) due to long-term exposure to PM2.5 in South Korea could change in the future according to the trend of change in the country’s population structure. Methods: The study employs a relative risk function, which accounts for age-specific relative risks, to assess the changes in premature deaths by age and region at the average annual PM2.5 concentration for 2022 and at PM2.5 concentration improvement levels. Premature deaths were estimated using the Global Exposure Mortality Model (GEMM). Results: The findings indicate that the increase in premature deaths resulting from the projected population structure changes up to 2050 would significantly outweigh the health benefits (reduction in premature deaths) compared to 2012. This is primarily attributed to the rising number of premature deaths among the elderly due to population aging. Furthermore, the study suggests that the effectiveness of the current domestic PM2.5 standard would be halved by 2050 due to the increasing impact of population aging on PM2.5-related mortality. Conclusions: The study highlights the importance of considering trends in population structure when evaluating the health benefits of air pollution reduction measures. By comparing and evaluating the health benefits in reflection of changes in population structure to the predicted PM2.5 concentration improvements at the provincial level, a more comprehensive assessment of regional air quality management strategies can be achieved.