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Trimetazidine (TMZ) has been demonstrated to have protective effects against myocardial ischemia/reperfusion (MI/R) injury. In the present study, we investigated the effects and the underlying mechanisms of TMZ on autophagy during MI/R in vivo and in vitro. In the in vivo study, an animal model of MI/R was induced by coronary occlusion. TMZ (20 mg/kg/day) protected the rat hearts from MI/R-induced heart failure by increasing ejection fraction and fractional shortening and decreasing end-systolic volume, end-diastolic volume, left ventricular (LV) internal diameter at systole, and LV internal diameter at diastole; it alleviated myocardial injury and oxidative stress by decreasing LDH, creatine kinase MB isoenzyme, ROS, and MDA levels and increasing SOD and glutathione peroxidase levels in plasma. TMZ also reduced myocardial infarct size and apoptosis. Moreover, TMZ markedly inhibited MI/R-induced autophagy by decreasing the protein and messenger RNA levels of LC3-II, Beclin1, ATG5, and ATG7 and the number of autophagosomes and by involving the AKT/mTOR pathway. Further, in the in vitro experiments, H9c2 cells were incubated with TMZ (40 μM) to explore the direct effects of TMZ following exposure to hypoxia and reoxygenation (H/R). TMZ increased cell viability and the concentration of intracellular SOD and inhibited H/R-induced cell apoptosis and ROS production. Moreover, TMZ decreased the number of autophagosomes and autophagy-related protein expression; it also upregulated p-AKT and p-mTOR expression. In addition, TMZ augmented Bcl-2 protein expression and diminished Bax protein expression, the Bax/Bcl-2 rate, and cleaved caspase-3 level. However, these effects on H9c2 cells were notably abolished by the PI3K inhibitor LY294002. In conclusion, our results showed that TMZ inhibited I/R-induced excessive autophagy and apoptosis, which was, at least partly, mediated by activating the AKT/mTOR pathway., Key Messages: TMZ improved cardiac function, alleviated myocardial injury and oxidative stress, and reduced the myocardial infarct area and apoptosis. TMZ inhibited MI/R-induced myocardial autophagy, H/R-induced H9c2 cell apoptosis, and autophagy flux. The effect of TMZ on autophagy was repressed by LY294002. TMZ protected against MI/R injury by inhibiting excessive autophagy via activating the AKT/mTOR pathway.