Objective To investigate the effect of activating α7 nicotinic acetylcholine receptor (α7nAchR) on cerebral cortical neurons injury induced by oxygen-glucose deprivation (OGD) and the possible mechanism. Methods Cerebral cortical neurons cultured for 7 d were randomly divided into three groups: control group, OGD group (Cells experienced a 12 h oxygen-glucose deprivation) and OGD group treated with PNU-282987 (Cells experienced a 12 h oxygen-glucose deprivation with PNU-282987 pretreatment for 24 h). Cell viability was determined by CCK-8 assay, lactate dehydrogenase (LDH) was examined to reflect cell injury, apoptosis and reactive oxygen species (ROS) production were analyzed by flow cytometry, and expression of hemeoxygenase-1 (HO-1) and hypoxia inducible factor-1α (HIF-1α) were detected by Western blotting analysis. Results OGD resulted in cell death, LDH increase, and cell apoptosis. Compared with the OGD group, PNU-282987 pretreated group had significantly increased cell survival (P<0.05), significantly decreased LDH level and ROS production (P<0.05), and significantly inhibited cell apoptosis (P<0.05). Meanwhile, HO-1 protein expression was significantly increased and HIF-1α protein expression was significantly reduced in PNU-282987 pretreated group compared with the OGD group (P<0.05). Conclusion Activation of α7nAchR can protect cerebral cortical neurons against OGD-induced injury, which may be related to the anti-oxidative stress.