The current study revealed that (1) ICS II, a naturally occurring SIRT3 agonist derived from Herbal Epimedii, exerts cardioprotection against MI in vivo and in vitro; (2) the protective effects of ICS II on MI are due to a reduction in oxidative stress injury and apoptosis through activating the AMPK/PGC-1α/SIRT3 pathway; (3) SIRT3 is necessarily required for the development of cardioprotective effects, and SIRT3 deficiency largely abrogates the cardioprotective effects of ICS II. Here, SIRT3 is linked to myocardial infarction.