The biggest mass extinction in the Phanerozoic, at the end of the Permian, has been associated with oceanic changes, but the exact dynamics are still debated. Intensified stratification, widespread anoxia, chemocline excursions, and large-scale ocean overturn events have all been invoked as contributors to the extinction. In this study the effects of possible changes in environmental conditions, such as an increase in nutrient input or dust fluxes into the ocean or an intensification of the biological pump, on Permian–Triassic ocean chemistry are investigated. Series of sensitivity experiments were performed with a fully coupled climate-carbon cycle model. None of the forcings alone generates extensive low-oxygen conditions in the deep sea. These are only simulated by an intense eutrophication in combination with an enhanced biological pump, but still confined to the central Panthalassic, Tethys, and the eastern Boreal Oceans. Our findings support the conclusions from a recent geochemical study of a Japanese deep Panthalassa section, that around the Permian-Triassic boundary, the oxygen minimum zone expanded considerably, while the deep Panthalassa remained ventilated. The warming-induced increase in low-oxygen conditions within the water column aggravated adverse existing conditions and likely contributed to the extinction peak. Upwelling of toxic water was probably regionally confined and hence not the main cause for the end-Permian marine and terrestrial mass extinction. Widespread deep-sea anoxia, generated by a strong increase in weathering and the related enhanced nutrient input into the oceans, is probably closely linked to the delayed recovery of species in the Early Triassic.