Human activity is exposing the Amazon rainforest to increasing stressors including plant damage due to elevated ozone (O3) pollution. O3-plant damage reduces plant photosynthesis and the land carbon sink thus increasing atmospheric CO2. Factors that control O3-plant damage in the Amazon have not been characterised so damage may be exacerbated by recurrent extreme drought and fires. We identify drivers of interannual variability in O3-plant damage using a land surface model validated against satellite products. We find that O3-plant damage increases with fire activity, with additional interactive effects during major droughts. The indirect increase in atmospheric CO2 from fire-driven O3-plant damage is ~50% the magnitude of direct CO2 emissions from fires in non-drought years, suggesting the negative impact of fires on the Amazon carbon budget is severely underestimated. During droughts, leaves close their stomata, which reduces O3 uptake and should protect against O3 damage. However, due to higher fire activity, and elevated O3 concentrations, O3-plant damage during droughts is up to 77 Tg-C (or over 2 times) greater than average. As droughts are set to become more frequent, our results demonstrate that high fire activity associated with drought increases the O3-plant damage risk to the rainforest, especially in remote areas.