Doxorubicin (DOX) induces oxidative stress leading to cardiotoxicity. Diosgenin,a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity.Our study was aimed to find out the protective effect of diosgenin against DOX-inducedcardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heartweight to body weight, and increases in the blood pressure and the serum levels of lactatedehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound(CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOXreduced activities of antioxidant enzymes, including superoxide dismutase (SOD) andglutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased theserum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relativesubstances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, andmitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), aninflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of