The Southern Annular Mode (SAM) is the main driver of climate variability at mid to high latitudes in the Southern Hemisphere, affecting wildfire activity, which in turn pollutes the air and contributes to human health problems and mortality, and potentially provides strong feedback to the climate system through emissions and land cover changes. Here we report the largest Southern Hemisphere network of annually resolved tree ring fire histories, consisting of 1,767 fire-scarred trees from 97 sites (from 22 °S to 54 °S) in southern South America (SAS), to quantify the coupling of SAM and regional wildfire variability using recently created multicentury proxy indices of SAM for the years 1531–2010 AD. We show that at interannual time scales, as well as at multidecadal time scales across 37–54 °S, latitudinal gradient elevated wildfire activity is synchronous with positive phases of the SAM over the years 1665–1995. Positive phases of the SAM are associated primarily with warm conditions in these biomass-rich forests, in which widespread fire activity depends on fuel desiccation. Climate modeling studies indicate that greenhouse gases will force SAM into its positive phase even if stratospheric ozone returns to normal levels, so that climate conditions conducive to widespread fire activity in SAS will continue throughout the 21st century.