Zhongfenggao (ZFG) is prescribed for the treatment of cerebrovascular diseases in critical projects of the State Administration of Traditional Chinese Medicine. ZFG has been found to nourish qi, activate blood circulation, remove blood stasis, dredge collaterals, and strengthen the brain and mind. The present study investigated the effects of ZFG on oxygen–glucose deprivation–reoxygenation (OGD/R) induced injury to brain microvascular endothelial cells (BMECs), and the mechanisms underlying such effects. BMECs are essential target cells of ischemic stroke. In order to simulate ischemic-like conditions in vitro , BMECs were exposed to glucose deprivation and hypoxia for 2 h. Results indicate that ZFG may protect OGD/R-induced injury to BMECs by promoting angiogenesis. Further, we observed that ZFG significantly inhibited apoptosis induced by OGD/R injury. ZFG significantly promoted migration and microtubule formation in BMECs under OGD/R conditions. Additionally, ZFG increased levels of the vascular endothelial growth factor (VEGF) significantly and activated the Notch and Wnt signaling pathways. The results of the present study indicate that ZFG may display a protective effect against OGD/R-induced BMECs injury by promoting angiogenesis via Notch and Wnt signaling pathways. These results provide novel insights into the mechanisms underlying the therapeutic action of ZFG which shows promise as a potential drug candidate for treating cerebral ischemia–reperfusion.