Propranolol, as the first generation of β-blocker family, was initially introduced in the clinical application for tachycardia and hypertension in the 1960s. However, the occasional discovery of propranolol in the involution of infantile hemangiomas (IHs) brought us a new perspective. IHs are the most common infantile tumor, affecting 4–10% newborns. So far, oral propranolol is the first-line medication for IHs treatment. At the same time, local injection and topical propranolol are developing. Despite the worldwide application, the precise mechanism of propranolol of IHs has not been completely studied. In this article, we reviewed and summarized the current information on pharmacology, mechanism, efficacy, and adverse effects of propranolol. Novel design of biomaterials and bioactive molecules are needed for new treatment and ideal pathway to attain the minimal effective treatment concentration and eliminate the adverse effects.