Natural products with antioxidative activities are widely applied to prevent and treat various oxidative stress related diseases, including ischemic heart disease. However, the cellular and molecular mechanisms of those therapies are still needed to be illustrated. In this study, we characterized the cardioprotective effects of Hongjingtian Injection (HJT), an extensively used botanical drug for treating coronary heart disease. The H/R-induced profound elevation of oxidative stress was suppressed by HJT. HJT also attenuates oxidative injury by promoting cell viability, intracellular ATP contents, and mitochondrial oxygen consumption. Validation experiments indicated that HJT inhibited H/R-induced apoptosis and regulated the expression of apoptosis-associated proteins Bcl-2 and cleaved caspase3. Interestingly, HJT significantly regulated the expression of autophagy-related proteins LC3, Beclin, and mTOR as well as ERK and AKT. We provide evidence that the mechanism involves activation of AKT/Beclin-1, AKT, and ERK/mTOR pathway in cardiomyocyte autophagy. Histological and physiological evaluation revealed that HJT significantly decreased the infarct area of the heart, improved cardiac function, and increased the expression of LC3B in a rat model of coronary occlusion. From the obtained data, we proposed that HJT diminished myocardial oxidative damage through regulating the balance of autophagy and apoptosis and reducing oxidative stress.