Ambient air quality across the southeastern US has improved substantially in recent decades. However, emissions from prescribed burns remain high, which may pose a substantial health threat. We employed a multistage modeling framework to estimate year-round, long-term effects of prescribed burns on air quality and premature deaths. The framework integrates a chemical transport model with a data-fusion approach to estimate 24-h average PM2.5 and maximum daily 8-h averaged O3 (MDA8-O3) concentrations attributable to prescribed burns for the period 2013–2020. The Global Exposure Mortality Model and a log-linear exposure–response function were used to estimate the premature deaths ascribed to long-term prescribed burn PM2.5 and MDA8-O3 exposure in ten southeastern states. Our results indicate that prescribed burns contributed on annual average 0.59 ± 0.20 µg/m3 of PM2.5 (∼10 % of ambient PM2.5) over the ten southeastern states during the study period. On average around 15 % of the state-level ambient PM2.5 concentrations were contributed by prescribed burns in Alabama (0.90 ± 0.15 µg/m3), Florida (0.65 ± 0.19 µg/m3), Georgia (0.91 ± 0.19 µg/m3), Mississippi (0.65 ± 0.10 µg/m3) and South Carolina (0.65 ± 0.09 µg/m3). In the extensive burning season (January–April), daily average contributions to ambient PM2.5 increased up to 22 % in those states. A large part of Alabama and Georgia experiences ≥3.5 µg/m3 prescribed burn PM2.5 over 30 days/year. Additionally, prescribed burns are responsible for an average increase of 0.32 ± 0.12 ppb of MDA8-O3 (0.8 % of ambient MDA8-O3) over the ten southeastern states. The combined effect of prescribed burn PM2.5 exposure, population growth, and increase of baseline mortality over time resulted in a total of 20,416 (95 % confidence interval (CI): 16,562–24,174) excess non-accidental premature deaths in the ten southeastern states, with 25 % of these deaths in Georgia. Prescribed burn MDA8-O3 was responsible for an additional 1,332 (95 % CI: 858–1,803) premature deaths in the ten southeastern states. These findings indicate significant impacts from prescribed burns, suggesting potential benefits of enhanced forest management strategies.