We explore how nuclear shut-downs in the United States could affect air pollution, climate and health with existing and alternative grid infrastructure. We develop a dispatch model to estimate emissions of CO2, NOx and SO2 from each electricity-generating unit, feeding these emissions into a chemical transport model to calculate effects on ground-level ozone and fine particulate matter (PM2.5). Our scenario of removing nuclear power results in compensation by coal, gas and oil, resulting in increases in PM2.5 and ozone that lead to an extra 5,200 annual mortalities. Changes in CO2 emissions lead to an order of magnitude higher mortalities throughout the twenty-first century, incurring US$11–180 billion of damages from 1 year of emissions. A scenario exploring simultaneous closures of nuclear and coal plants redistributes health impacts and a scenario with increased penetration of renewables reduces health impacts. Inequities in exposure to pollution are persistent across all scenarios—Black or African American people are exposed to the highest relative levels of pollution.