Background: Saponins from Rhizoma Panacis Majoris (SRPM) are confirmed to have cardioprotective effect against myocardial ischemia injury by reducing oxidative stress, while its underlying mechanism has not been elucidated until recently. Objective: The objective of this study was to investigate the SRPM's cardioprotection and elucidate its underlying mechanisms. Materials and Methods: Adult male rats were received SRPM treatment in the presence or the absence of the silent information regulator 1 (Sirt1) inhibitor Ex-527 or nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ATRA for 14 days and subjected to myocardial ischemia for 0.5 h and then 2 h reperfusion. Cardiac function, infarct size, antioxidant enzyme activities, ROS level and the related mRNA and protein expressions of antiapoptosis protein Bcl-2, proapoptosis protein Bax, caspase-3, caspase-9, Sirt1 and Nrf2-relatived signaling pathways were assessed. Results: SRPM was confirmed to have cardioprotective effects by ameliorating cardiac function, decreasing infarct size, reducing serum creatine kinase (CK), creatine kinase isoenzyme, lactate dehydrogenase and ROS releases and malondialdehyde level, raising total antioxidant capacity, superoxide dismutase, glutathione peroxidase, catalase activities, upregulating myocardial Sirt1, Nrf2, Bcl-2 protein and manganese superoxide dismutase, heme oxygenase-1, NAD(P)H-quinone oxidoreductase 1 and γ-glutamylcysteine synthetase mRNA expressions and downregulating acetylated forkhead box O 1, acetylated peroxisome proliferator-activated receptor γ coactivator 1α, Bax, cleaved caspase-3 and cleaved caspase-9 protein expressions; histopathological observations provided supportive evidence for the aforementioned results. Interestedly, its protective effects were significantly blocked for its combination with Ex-527 or ATRA. Conclusion: The studies demonstrated that SRPM exerted beneficially protective effects on myocardial ischemia/reperfusion injury. It was possibly related to reducing oxidative stress damage by activations of Sirt1 and Nrf2-related antioxidant signaling pathways.