Ischemia reperfusion injury, an important clinical problem that is caused by interruption of blood supply to tissue followed by blood reflow into the exposed area, is commonly seen in clinic and is difficult to avoid. Klotho, an anti-aging protein, possesses a variety of functions including anti-oxidative stress, anti-apoptosis, anti-inflammation, calcium overload inhibition and so on. This review summarizes the current knowledge of the involvement of Klotho in ischemia reperfusion injury and its possible mechanisms, attempting to provide some basis for the research and development of new drugs for the treatment of ischemia reperfusion injury.