Porphyrins, a class of cyclic compounds featuring a metal ion at the core of their macrocyclic structure, have long been recognized as indispensable cofactors in natural enzymatic processes. These porphyrin-based enzymes enable a wide variety of complex biochemical transformations under mild conditions with high yield, regioselectivity and stereoselectivity. As mimics of P450 enzymes, the integration of porphyrins into artificial enzymatic systems to catalyze unnatural organic reactions represents a rapidly advancing research area. Such reactions, those typically catalyzed by small molecule catalysts, are of significant interest in synthetic chemistry. This mini-review explores the role of porphyrins in both enzyme-catalyzed natural and unnatural organic reactions, with a focus on their use as cofactors in engineered metalloenzymes.