Myocardial ischemia-reperfusion (MI/R) is a major risk factor for cardiovascular disease. At present, reducing oxidative stress and apoptosis is a crucial therapeutic strategy for ameliorating MI/R injury. However, there is a lack of drugs targeting oxidative stress and apoptosis for the clinical therapy of MI/R. Bergenin is a reportedly effective agent with antioxidative and antiapoptotic activity against acute injury. Nevertheless, the roles and potential mechanisms of bergenin against MI/R injury remain unknown. Here, we hypothesized that bergenin attenuated MI/R-induced apoptosis and reactive oxygen species (ROS) production via SIRT1. Mice were subjected to MI/R and treated with bergenin, after which the cardiac function, cardiomyocyte apoptosis, LDH release, and MDA content were evaluated. In vitro, myocardial injury model of H9c2 cells was induced by simulated ischemia/reperfusion (SI/R), apoptosis and oxidative stress was decreased after treated with bergenin. Bergenin significantly reduced myocardial apoptosis and ROS generation in vitro and improved cardiac function in vivo. Intriguingly, bergenin remarkably decreased apoptosis in cardiac tissue accompanied by SIRT1 upregulation following MI/R injury. Further studies showed that inhibiting SIRT1 blocked bergenin’s beneficial impact against apoptosis following SI/R injury through excessive oxidative stress and depression of the Bcl2 to Bax ratio. Collectively, these findings indicate that bergenin alleviates MI/R injury by ameliorating myocardial apoptosis and oxidative damage via the SIRT1 signaling pathway.