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Oxygen and glucose deprivation and reperfusion (OGD/R) injury contributes to the pathophysiology after ischemic stroke, which needs to urgently develop treatment strategies. Previous studies have demonstrated that autophagy in reperfusion period exerted adverse effects on the cerebral ischemic injury. Ginsenoside monomer compound K (CK) is the main intestinal metabolite of ginseng that exerts the pharmacological activities and has a protective effect against cerebral OGD/R injury. However, the specific molecular mechanism of CK protects against OGD/R injury in neurons is still unclear. In this study, cell viability, reactive oxygen species (ROS) generation, Ca2+ overload, mitochondrial membrane potential depolarization, autophagy and apoptosis were investigated in OGD/R-induced neuronal cells injury after pretreatment with CK and in combination with BML-275 or rapamycin. Our study found that pretreatment with CK protected neurons against OGD/R injury by increasing cell viability and decreasing the ROS generation, mitochondrial damage, and Ca2+ overload. Moreover, CK cut down autophagy-mediated apoptosis via promoting the process of forming autophagosomes into phagocytic precursors. Furthermore, our study clarified the neuroprotective of CK against OGD/R-induced neural autophagy and apoptosis through the regulation of the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway. Taken together, our study provides credible experimental evidence and explains the potential molecular mechanism of CK as one of the main bioactive ingredients of ginseng for the treatment of cerebral ischemia/reperfusion injury. Unlabelled Image • Compound K decreased the ROS generation, mitochondrial damage and Ca2+ overload. • Compound K reduced apoptosis and autophagy by regulating the formation of phagocytic precursors to autophagosomes. • Compound K regulated the AMPK-mTOR pathway in OGD/R-induced neuronal cells injury. • Compound K is the key bioactive ingredients of ginseng for the treatment of cerebral ischemia stoke. [ABSTRACT FROM AUTHOR]