Atmospheric CO2 concentrations are predicted to double within the next century. Despite this trend, the extent and mechanisms through which elevated CO2 affects plant diseases remain uncertain. In this study, we assessed how elevated CO2 affects a foliar fungal pathogen, Phyllosticta minima, of Acer rubrum growing in the understory at the Duke Forest free-air CO2 enrichment experiment in Durham, North Carolina. Surveys of A. rubrum saplings in the 6th, 7th, and 8th years of the CO2 exposure revealed that elevated CO2 significantly reduced disease incidence, with 22%, 27%, and 8% fewer saplings and 14%, 4%, and 5% fewer leaves infected per plant in the three consecutive years, respectively. Elevated CO2 also significantly reduced disease severity in infected plants in all years (e.g. mean lesion area reduced 35%, 50%, and 10% in 2002, 2003, and 2004, respectively). To assess the mechanisms underlying these changes, we combined leaf structural, physiological and chemical analyses with growth chamber studies of P. minima growth and host infection. In vitro exponential growth rates of P. minima were enhanced by 17% under elevated CO2, discounting the possibility that disease reductions were because of direct negative effects of elevated CO2 on fungal performance. Scanning electron micrographs (SEM) verified that conidia germ tubes of P. minima infect A. rubrum leaves by entering through the stomata. While stomatal size and density were unchanged, stomatal conductance was reduced by 21–36% under elevated CO2, providing smaller openings for infecting germ tubes. Reduced disease severity under elevated CO2 was likely due to altered leaf chemistry and reduced nutritive quality; elevated CO2 reduced leaf N by 20% and increased the C : N ratio by 20%, total phenolics by 15%, and tannins by 14% (P<0.05 for each factor). The potential dual mechanism we describe here of reduced stomatal opening and altered leaf chemistry that results in reduced disease incidence and severity under elevated CO2 may be prevalent in many plant pathosystems where the pathogen targets the stomata.