Geochemical, biomarker, and isotopic evidence suggests that the end-Permian was characterized by extreme oceanic anoxia that may have led to hydrogen sulfide buildup and mass extinction. We use an earth system model to quantify the biogeochemical and physical conditions necessary for widespread oceanic euxinia and hydrogen sulfide release to the atmosphere. Greater than threefold increases in ocean nutrient content combined with nutrient-trapping ocean circulation cause surface-water H2S accumulation in the paleo–Tethys Ocean and in areas of strong upwelling. Accounting for the presence of sulfide-oxidizing phototrophs in the model suppresses but does not prevent widespread release of H2S to the atmosphere. Evidence from the geologic record is consistent with modeled geochemical distributions of widespread nutrient-induced euxinia during the end-Permian, suggesting H2S toxicity and hypercapnia may have provided the kill mechanism for extinction.