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Wildfires, exacerbated by extreme weather events and land use, threaten to change the Amazon from a net carbon sink to a net carbon source. Here, we develop and apply a coupled ecosystem-fire model to quantify how greenhouse gas-driven drying and warming would affect wildfires and associated CO2 emissions in the southern Brazilian Amazon. Regional climate projections suggest that Amazon fire regimes will intensify under both low- and high-emission scenarios. Our results indicate that projected climatic changes will double the area burned by wildfires, affecting up to 16% of the region's forests by 2050. Although these fires could emit as much as 17.0 Pg of CO2 equivalent to the atmosphere, avoiding new deforestation could cut total net fire emissions in half and help prevent fires from escaping into protected areas and indigenous lands. Aggressive efforts to eliminate ignition sources and suppress wildfires will be critical to conserve southern Amazon forests.