When histiocyte are ischemic for a certain time and blood supply is suddenly restored, the pathological condition of rapidly aggravated tissue damage is called ischemia reperfusion injury, which is mainly caused by a large amount of Ca2+ influx and oxygen free radicals attacking ischemic histiocyte. Ischemia reperfusion injury can increase the incidence rate and mortality of some diseases, such as acute myocardial infarction, ischemic stroke, acute renal injury, intestinal obstruction, hyperkalemia and multiple organ failure, and it also brings great challenges to surgery such as organ transplantation. However, the current treatment methods for ischemia-reperfusion are still very limited. Fortunately, increasing evidence suggests that reasonable concentrations of hydrogen sulfide may play a powerful organ protective role in ischemia-reperfusion injury, mainly through mechanisms such as anti apoptotic, antioxidant, stress reduction, regulation of autophagy, and inhibition of inflammation. Therefore, hydrogen sulfide has profound clinical conversion prospects in the treatment of I/R injury. This article systematically summarizes the generation and physiological effects of endogenous hydrogen sulfide, as well as its protective mechanisms in different systems such as the heart, brain, kidney, liver, retina, and testes. In addition, the clinical transformation prospects and current challenges of hydrogen sulfide in ischemia-reperfusion injury were discussed.