20(S)-protopanaxadiol (PPD) is an active natural product which is transformed from protopanaxadiol-type ginsenosides. The present study was conducted to evaluate the effects of PPD on myocardial ischemia/reperfusion (I/R) injury in a rat model. PPD (20mg/kg) or positive-control drug Diltiazem (10mg/kg) was administered daily for 7 days before left anterior descending I/R operation. After 2-hour reperfusion, changes of cardiac morphology, structure, and function were evaluated by HE staining and echocardiography. Myocardial infarct size was assessed using nitroblue tetrazolium staining. The activities of cardiac enzymes in serum were also evaluated. Cardiomyocyte apoptosis was detected using the terminal dUTP nick end labelling (TUNEL) assay. The extent of oxidative stress was evaluated according to the activities of superoxide dismutase (SOD) and glutathione per oxidase (GPx) and the levels of malondialdehyde (MDA). Western blot and immunohistochemistry were used to determine the expression of apoptosis associated proteins, including Bcl-2, Bax, cleaved Caspase-3, cleaved Caspase-9, and cytochrome C. According to the results, PPD reduced I/R‑induced increases in myocardial infarct size and improved cardiac function. Furthermore, PPD decreased cardiomyocyte apoptosis on TUNEL staining, which was verified by increased Bcl-2, and decreased expression of Bax, cytochrome C, cleaved Caspase-9, and cleaved Caspase-3 in I/R rat myocardium. Additionally, PPD reduced MDA levels and increased the anti-oxidative capacity by upregulating the activities of SOD and GPx. Taken together, the results suggest that PPD serves a protective role against oxidative stress and cardiomyocyte apoptosis during myocardial ischemia/reperfusion injury.