Abstract Vegetation fires across the tropics emit fine particulate matter (PM_2.5) to the atmosphere, degrading regional air quality and impacting human health. Extensive vegetation fires occur regularly across the Amazon basin, but there have been no detailed assessments of the impacts on air quality or human health. We used updated exposure-response relationships and a regional climate-chemistry model, evaluated against a comprehensive set of observational data, to provide the first in-depth assessment of the potential public health benefits due to fire prevention across the Amazon Basin. We focused on 2012, a year with emissions similar to the 11-year average (2008 to 2018). Vegetation fires contributed >80% of simulated dry season mean surface PM_2.5 in the western Amazon region particularly in Bolivia and Brazilian states of Rondônia, Acre, and Mato Grosso. We estimate that the prevention of vegetation fires would have averted 16 800 (95UI: 16 300–17 400) premature deaths and 641 000 (95UI: 551 900–741 300) disability adjusted life years (DALYs) across South America, with 26% of the avoided health burden located within the Amazon Basin. The health benefits of fire prevention in the Amazon are comparable to those found in Equatorial Asia.