The cytochromes P450 are versatile enzymes involved in various catalytic oxidation reactions, such as hydroxylation, epoxidation and dehydrogenation. In this work, we present combined experimental and theoretical studies on the change of regioselectivity in cyclohexadiene oxidation (i.e., epoxidation vs dehydrogenation) by oxoiron(IV) porphyrin complexes bearing different porphyrin ligands. Our experimental results show that meso-substitution of the porphyrin ring with electron-withdrawing substituents leads to a regioselectivity switch from dehydrogenation to epoxidation, affording the formation of epoxide as a major product. In contrast, electron-rich iron porphyrins are shown to produce benzene resulting from the dehydrogenation of cyclohexadiene. Density functional theory (DFT) calculations on the regioselectivity switch of epoxidation vs dehydrogenation have been performed using three oxoiron(IV) porphyrin oxidants with hydrogen atoms, phenyl groups, and pentachlorophenyl (ArCl5) groups on the meso-position. The DFT studies show that the epoxidation reaction by the latter catalyst is stabilized because of favorable interactions of the substrate with halogen atoms of the meso-ligand as well as with pyrrole nitrogen atoms of the porphyrin macrocycle. Hydrogen abstraction transition states, in contrast, have a substrate-binding orientation further away from the porphyrin pyrrole nitrogens, and they are much less stabilized. Finally, the regioselectivity of dehydrogenation versus hydroxylation is rationalized using thermodynamic cycles.