Making accurate, quantitative predictions of chemical reactivity based on molecular structure is an unsolved problem in chemical synthesis, particularly for complex molecules. We report an approach to reactivity prediction for catalytic reactions based on quantitative structure-reactivity models for a key step common to many catalytic mechanisms. We demonstrate this approach with a mechanistically based model for the oxidative addition of (hetero)aryl electrophiles to palladium(0), which is a key step in myriad catalytic processes. This model links simple molecular descriptors to relative rates of oxidative addition for 79 substrates, including chloride, bromide and triflate leaving groups. Because oxidative addition often controls the rate and/or selectivity of palladium-catalyzed reactions, this model can be used to make quantitative predictions about catalytic reaction outcomes. Demonstrated applications include a multivariate linear model for the initial rate of Sonogashira coupling reactions, and successful site-selectivity predictions for Suzuki, Buchwald-Hartwig, and Stille reactions of multihalogenated substrates relevant to the synthesis of pharmaceuticals and natural products.