Exposure to ozone and fine particle (PM2.5) air pollution results in premature death. These pollutants are predominantly secondary in nature and can form from nitrogen oxides (NOX), sulfur oxides (SOX), and volatile organic compounds (VOCs). Predicted health benefits for emission reduction scenarios often incompletely account for VOCs as precursors as well as the secondary organic aerosol (SOA) component of PM2.5. Here, we show that anthropogenic VOC emission reductions are more than twice as effective as equivalent fractional reductions of SOX or NOX at reducing air pollution-associated cardiorespiratory mortality in the United States. A 25% reduction in anthropogenic VOC emissions from 2016 levels is predicted to avoid 13,000 premature deaths per year, and most (85%) of the VOC-reduction benefits result from reduced SOA with the remainder from ozone. While NOX (-5.7 ± 0.2 % yr-1) and SOX (-12 ± 1 % yr-1) emissions have declined precipitously across the U.S. since 2002, anthropogenic VOC emissions (-1.8 ± 0.3 % yr-1) and concentrations of non-methane organic carbon (-2.4 ± 1.0 % yr-1) have changed less. This work indicates preferentially controlling VOCs could yield significant benefits to human health.