The YiQiFuMai powder injection (YQFM), a Traditional Chinese Medicine (TCM) prescription redeveloped based on the wellknown TCM formula Shengmaisan, showed a wide range of pharmacological activities in cardiovascular diseases in clinic.However, its role in protection against myocardial ischemia/reperfusion (MI/R)injury has not been elucidated.The present study not only evaluated the cardioprotective effect of YQFM from MI/R injury but also investigated the potential molecular mechanisms in vivo and in vitro.The mouse model of MI/R injury was induced by a transient vessel occlusion for 30 rain and reperfusion for 24 h.The myocardium infarct size, production of lactate dehydrogenase (LDH), creatine kinase (CK), TUNEL staining and caspase3 activity were measured.AMPKα and phosphoAMPKα was analyzed by Western blot.We further verified the protective effect and potential molecular mechanisms of YQFM in an in vitro model of simulated ischemia and reperfusion (SI/R) in H9c2 cardiomyocytes.Cell viability was determined, and cell apoptosis were measured by Hoechst 33342staining and Flow cytometry.Mitochondrial membrane potential (△Ψm) was measured, and ATP content was quantified by bioluminescent assay.Expression of apoptosisrelated proteins including Caspase3, Bc12, Bax,AMPKα and phosphoAMPKα was analyzed by Western blot.AMPKα siRNA transfection was also applied to the mechanism elucidation.YQFM significantly reduced myocardium infarct size and the production of LDH, CK in serum, and also produced a significant decrease.of apoptotic index which was confirmed by TUNEL staining and the changes of caspase3 activity.In addition, pretreatment with YQFM markedly improved cell viability and decreased LDH release.Moreover, YQFM inhibited H9c2 apoptosis, blocked the expression of caspase3 and modulated Bcl2 and Bax proteins, leading to an increased mitochondrial membrane potential and cellular ATP content.Mechanistically, YQFM activated AMPK signaling pathways while pretreatment with AMPK inhibitor compound C and application of transfection with AMPKα siRNA attenuated the antiapoptotic effect of YQFM.Our results indicated that YQFM could provide significant cardioprotection against MI/R injury, and potential mechanisms might to suppression of cardiomyocytes apoptosis at least in part through activating the AMPK signaling pathways.