Periodontitis is one of the most prevalent inflammatory disease worldwide, which affects 11% of the global population and is a major cause of tooth loss. Recently, oxidative stress (OS) has been found to be the pivital pathophysiological mechanism of periodontitis, and overactivated OS will lead to inflammation, apoptosis, pyroptosis and alveolar bone resorption. Interestingly, heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme degradation, can exert antioxidant activites through its products—carbon monoxide (CO), Fe2+, biliverdin and bilirubin in the inflammatory microenvironment, thus exhibiting anti-inflammatory, anti-apoptotic, anti-pyroptosis and bone homeostasis-regulating properties. In this review, particular focus is given to the role of HO-1 in periodontitis, including the spatial-temporal expression in periodental tissues and pathophysiological mechanisms of HO-1 in periodontitis, as well as the current therapeutic applications of HO-1 targeted drugs for periodontitis. This review aims to elucidate the potential applications of various HO-1 targeted drug therapy in the management of periodontitis, investigate the influence of diverse functional groups on HO-1 and periodontitis, and pave the way for the development of a new generation of therapeutics that will benefit patients suffering from periodontitis.