The association between PM2.5 and non-respiratory infections is unclear. Using data from Medicare beneficiaries and high-resolution datasets of PM2.5 and its constituents across 39,296 ZIP codes in the U.S between 2000 and 2016, we investigated the associations between annual PM2.5, PM2.5 constituents, source-specific PM2.5, and hospital admissions from non-respiratory infections. Each standard deviation (3.7-μg m−3) increase in PM2.5 was associated with a 10.8% (95%CI 10.8–11.2%) increase in rate of hospital admissions from non-respiratory infections. Sulfates (30.8%), Nickel (22.5%) and Copper (15.3%) contributed the largest weights in the observed associations. Each standard deviation increase in PM2.5 components sourced from oil combustion, coal burning, traffic, dirt, and regionally transported nitrates was associated with 14.5% (95%CI 7.6–21.8%), 18.2% (95%CI 7.2–30.2%), 20.6% (95%CI 5.6–37.9%), 8.9% (95%CI 0.3–18.4%) and 7.8% (95%CI 0.6–15.5%) increases in hospital admissions from non-respiratory infections. Our results suggested that non-respiratory infections are an under-appreciated health effect of PM2.5.