Hypoxia-inducible factors (HIFs) play a crucial role in cellular responses to low oxygen levels during myocardial ischemia and reperfusion injury. HIF stabilizers, originally developed for treating renal anemia, may offer cardiac protection in this context. This narrative review examines the molecular mechanisms governing HIF activation and function, as well as the pathways involved in cell protection. Furthermore, we analyze the distinct cellular roles of HIFs in myocardial ischemia and reperfusion. We also explore potential therapies targeting HIFs, emphasizing their possible benefits and limitations. Finally, we discuss the challenges and opportunities in this research area, underscoring the need for continued investigation to fully realize the therapeutic potential of HIF modulation in managing this complex condition.