Under current global warming, South America (SA) has been experiencing severe compound drought-heatwave (CDHW) conditions, which, in turn, exacerbate fire risk. A recent showcase is the unprecedented Pantanal 2020 fire season (P20F), when one-third of the biome was burned, with reported local impacts on the ecosystem, public health, and economy. Nevertheless, the extent to which this event led to long-range ripple effects remains unknown. Here, we explored a cascade chain of hazards along the continent associated with the CDHW-fires from P20F, integrating observational, satellite-based, and reanalysis data, models, and death records. We showed that CDHW-fire-related smoke transport episodes triggered high PM2.5 levels in the SA's most populated area, surpassing the World Health Organization’s guidelines by up to 600%. Such smoke-induced air pollution conditions coincided with widespread heatwaves in the affected remote areas, amplifying health risks. The mortality burden attributable to this multi-hazard short-term (14 days) exposure was estimated to be 2,150 premature deaths (21% increase above expected levels). Our findings highlight that the impacts of CDHW-fire events in SA are beyond the local level, implying growing challenges for risk management and public health and the need for governance based on telecoupled flows, linking different systems over multiple scales.