The regio‐ (and stereo‐)selectivity and specific activity of cytochrome P450s are determined by the accessibility of potential sites of metabolism (SOMs) of the bound substrate relative to the heme, and the activation barrier of the regioselective oxidation reaction(s). The accessibility of potential SOMs depends on the relative binding free energy (ΔΔGbind) of the catalytically active substrate‐binding poses, and the probability of the substrate to adopt a transition‐state geometry. An established experimental method to measure activation energies of enzymatic reactions is the analysis of reaction rate constants at different temperatures and the construction of Arrhenius plots. This is a challenge for multistep P450‐catalyzed processes that involve redox partners. We introduce a modified Arrhenius approach to overcome the limitations in studying P450 selectivity, which can be applied in multiproduct enzyme catalysis. Our approach gives combined information on relative activation energies, ΔΔGbind values, and collision entropies, yielding direct insight into the basis of selectivity in substrate conversion. Selectivity insight: Measuring the activation energies of enzymatic reactions often involves analyzing reaction rate constants at various temperatures and constructing Arrhenius plots. This is a challenge for multistep cytochrome P450‐catalyzed processes that involve redox partners. Herein we present a modified Arrhenius approach to enable the study of thermodynamic determinants of selectivity in P450‐catalyzed substrate conversion.