This study was designed to investigate the effect of naringin in oxygen-glucose deprivation/reoxygenation (OGD/R) model and its mechanism. The target gene of naringin and the enriched pathways of the gene were searched and identified using bioinformatics analysis. Then OGD/R model was built using PC12 cells, after which the cells were treated with different concentrations of naringin. Subsequently, cell proliferation and apoptosis were evaluated by cell counting kit-8 (CCK-8) and flow cytometry assays, respectively. Meanwhile, the expression of NFKB1 in PC12 cells underwent OGD/R-induced injury was detected by qRT-PCR, while apoptosis-related and pathway-related proteins were checked by Western blot. DCF-DA kit was utilized to measure the level of ROS. Our results revealed that NFKB1, which was upregulated in MACO rats and OGD/R-treated PC12 cells, was a target gene of naringin. Naringin could alleviate OGD/R-induced injury via promoting the proliferation, and repressing the apoptosis of PC12 cells through regulating the expression of NFKB1 and apoptosis-associated proteins and ROS level. Besides, the depletion of NFKB1 was positive to cell proliferation but negative to cell apoptosis. Moreover, the depletion of NFKB1 enhanced the influences of naringin on cell proliferation and apoptosis as well as the expression of apoptosis-related proteins and ROS level. Western blotting indicated that both naringin treatment and depletion of NFKB1 could increase the expression of HIF-1 alpha, p-AKT, and p-mTOR compared with OGD/R group. What's more, treatment by naringin and si-NFKB1 together could significantly increase these effects. Nevertheless, the expression of AKT and mTOR among each group was almost not changed. In conclusion, naringin could prevent the OGD/R-induced injury in PC12 cells in vitro by targeting NFKB1 and regulating HIF-1 alpha/AKT/mTOR-signaling pathway, which might provide novel ideas for the therapy of cerebral ischemia-reperfusion (I/R) injury.