Objective To investigate the myocardial protective effect and possible regulatory mechanism ofHonokiol (HKL) on Acute Myocardial Infarction (AMI) in vivo . Methods Eighty male C57BL/6J mice were randomlydivided into the following groups: Sham (Sham) group, Myocardial Infarction model and Vehicle (MI + V) group, Myocardial Infarction model and HKL treatment (MI + HKL) group, Myocardial Infarction model, HKL treatment andSirtuin-1(SIRT1) inhibitor (selisistat, EX527)(MI + HKL + EX) group, with twenty mice in each group. The mortalityof the mice during modeling stage was recorded after the operation. The echocardiogram and serum samples of the mice were gathered on the 28th day after the operation. The inflammatory indexes in the serum were detected by enzyme linkedimmunosorbent assay (ELISA). Besides, dihydroethidium staining(DHE) was utilized to display the intensity of reactiveoxygen species in myocardial tissue. Apoptosis ratio was evaluated by detection of terminal-deoxynucleoitidyl transferasemediated nick end labeling(TUNEL)and the expression of other target molecules was detected by Western Blot. Results Compared with the model group, the heart function of MI mice treated with oral HKL was significantly improved, the levelsof inflammatory factors in serum were decreased. Additionally, cardiomyocyte apoptosis rate and reactive oxygen species inmyocardial tissue were reduced. Simultaneously, the expression of SIRT1 was significantly up-regulated while theexpression of Ac-Foxo1 protein was down-regulated, which were reversed by SIRT1 inhibitor (EX527) ( P < 0. 05). Conclusions Oral HKL attenuate myocardial damage induced by myocardial infarction and significantly improvemyocardial function, which may be regulated by the SIRT1/ Ac-Foxo1 signal.