Exposure to fine particulate matter (PM 2.5 ) from fuel combustion significantly contributes to global and US mortality. Traditional control strategies typically reduce emissions for specific air pollutants and sectors to maintain pollutant concentrations below standards. Here we directly set national PM 2.5 mortality cost reduction targets within a global human-earth system model with US state-level energy systems, in scenarios to 2050, to identify endogenously the control actions, sectors, and locations that most cost-effectively reduce PM 2.5 mortality. We show that substantial health benefits can be cost-effectively achieved by electrifying sources with high primary PM 2.5 emission intensities, including industrial coal, building biomass, and industrial liquids. More stringent PM 2.5 reduction targets expedite the phaseout of high emission intensity sources, leading to larger declines in major pollutant emissions, but very limited co-benefits in reducing CO 2 emissions. Control strategies limiting health damages achieve the greatest emission reductions in the East North Central and Middle Atlantic states.