Astragaloside IV is a natural saponin purified from Astragalus membranaceus that exerts a promising effect on Alzheimer’s disease (AD). This study explored its effects on cerebral ischemic injury. SD rats were randomized into sham-operation group, Vehicle (MCAO) group and Astragaloside IV groups (25, 50 and 100 mg/kg, respectively), followed by analysis of neurological deficit, brain edema, infarct volume and neuronal apoptosis. In addition, autophagy was also monitored using an electron microscope. Finally, the functional mechanism for Astragaloside IV was studied via Western-blotting. Astragaloside IV can ameliorate brain ischemia/reperfusion injury and consequent neurological malfunction. The induction of autophagy is a participant in the protective mechanism for SH-SY5Y cells against brain ischemia/reperfusion damage. Additionally, Astragaloside IV can trigger autophagy by manipulating AMPK/mTOR signal pathway. For SH-SY5Y cells, Astragaloside IV ameliorates oxygen-glucose deprivation-reoxygenation damage via restraining of AMPK/mTOR-triggered autophagic process and mitochondria-mediated apoptotic activity. In conclusion, Astragaloside IV can execute a neuroprotective effect on cerebral ischemia, implying that it might be a promising candidate drug in the therapy and prophylaxis of ischemic stroke.