Ischemia-reperfusion injury is a complex hemodynamic pathology that is a leading cause of death worldwide and occurs in many body organs. Numerous studies have shown that mitochondria play an important role in the occurrence mechanism of ischemia-reperfusion injury and that mitochondrial structural abnormalities and dysfunction lead to the disruption of the homeostasis of the whole mitochondria. At this time, mitochondria are not just sub-organelles to produce ATP but also important targets for regulating ischemia-reperfusion injury; therefore, drugs targeting mitochondria can serve as a new strategy to treat ischemia-reperfusion injury. Based on this view, in this review, we discuss potential therapeutic agents for both mitochondrial structural abnormalities and mitochondrial dysfunction, highlighting the application and prospects of targeted mitochondrial drugs in the treatment of ischemia-reperfusion injury, and try to provide new ideas for the clinical treatment of the ischemia-reperfusion injury.