Patterns of taxonomic and ecologic selectivity are the most direct record of processes influencing survival during background and mass extinctions. The Guadalupian (Capitanian) and end-Permian (Changhsingian) extinctions have both been linked to environmental degradation from eruption of large flood basalts; however, the extent to which taxonomic selectivity conforms to the expected stresses remains incompletely understood because many of the relevant biological traits are mutually correlated. Here we use a large occurrence-based database to quantify extinction selectivity during background and mass extinction intervals from the Kungurian (latest Early Permian) to Changhsingian. Our multiple logistic regression analysis confirms that the end-Permian extinction was a physiological crisis, selecting against genera with poorly buffered respiratory physiology and calcareous shells. Genera with unbuffered physiology also fared poorly in the Guadalupian extinction, consistent with recognition of a pronounced crisis only among protists and reef-builders and implying similar respiratory physiological stresses. Despite sharing a similar trigger, the end-Permian extinction was considerably more severe than the Guadalupian or other Phanerozoic physiological crises. Its magnitude may have resulted from a larger environmental perturbation, although the combination of warming, hypercapnia, ocean acidification, and hypoxia during the end-Permian extinction likely exacerbated the crisis because of the multiplicative effects of those stresses. Although ocean carbon cycle and evolutionary changes have reduced the sensitivity of modern ecosystems to physiological stresses, extant marine invertebrates face the same synergistic effects of multiple stressors that were so severe during the end-Permian extinction.