Heme oxygenase (HO) enzyme catalyzes the degradation of free heme to biliverdin, CO, and Fe in three consecutive steps. The up-regulated activity of heme oxygenase is thought to be correlated with the antioxidant role of HO-1 in an oxidative stress environment. HO enzyme regiospecifically oxidizes heme at α meso position in a three-oxygenation step process. Although hydroperoxy-ferric heme, generated in the first step, has been indicated as an intermediate in most heme enzymes, heme degradation only occurs in HO reaction. Therefore, heme oxygenase must catalyze the reaction through a mechanism different from the other heme enzymes. Also, there are uncertainties in the second step of the process regarding electron requirement and a binding site for O₂ molecule. In this article, we review researchers’ attempts to elucidate complicated heme catabolism mechanism, especially in the less known process steps. A more detailed understanding of the reaction mechanism can help researchers to shed light on the determinants of specificity and better contribute to developing new medicines. Special focus is placed on the experimental and theoretical studies on the structural characteristics and electronic configurations of heme catabolism intermediates catalyzed by HO. An overview of the non-precedent route for the direct conversion of oxophlorin to biliverdin is also presented.