Rapid climate change at the end of the Permian Period (similar to 252 million years ago) is the hypothesized trigger for the largest mass extinction in Earth's history. We present model simulations of the Permian/Triassic climate transition that reproduce the ocean warming and oxygen (O-2) loss indicated by the geologic record. The effect of these changes on animal survival is evaluated using the Metabolic Index (Phi), a measure of scope for aerobic activity governed by organismal traits sampled in diverse modern species. Modeled loss of aerobic habitat predicts lower extinction intensity in the tropics, a pattern confirmed with a spatially explicit analysis of the marine fossil record. The combined physiological stresses of ocean warming and O-2 loss can account for more than half the magnitude of the "Great Dying."