Abstract: To investigate the protective effect and mechanism of semen ziziphi spinosae (SZS) on ischemic injury in hCMEC/D3 cells, the cells were divided into control, oxygen-glucose deprivation/reperfusion model, three doses of SZS drug and positive drug groups. The levels of inflammatory cytokines in the cells were measured by ELISA. Angiogenesis and migration abilities were evaluated using tube formation and scratch wound healing assays, respectively. Cell apoptosis was assessed by measuring Caspase-3 activity with a kit. The key proteins expression in the PI3K/AKT/NF-κB signaling pathway was analyzed by western blot. Compared with control group, model group significantly increased IL-1β (31.0%) and IL-6 (39.4%) (P<0.01) levels. Three doses of SZS drug reduced the levels of inflammatory factors, promoted cell migration (P<0.01), enhanced tube formation capacity and inhibited cells apoptosis. With VEGFR2 inhibitor Apatinib, it was confirmed that SZS alleviated ischemic injury via the PI3K/AKT/NF-κB pathway, exhibiting vascular protective effects.