Objective To investigate the effect and mechanism of exogenous cholecystokinin octapeptide(CCK-8)on neuronal apoptosis induced by glutamate in the rat cerebral cortex in vitro. Methods Rat cortical neurons cultured in vitro were treated with various concentrations of CCK-8. An MTT assay was used to assess cell survival and screen the appropriate concentration. Rat cortical neurons were treated with glutamic acid(Glu)to establish a neuron injury model and The Ca²⁺ level was assessed by Flou-4 staining. Bcl-2 and Bax mRNA expression was assessed by Real-time quantitative PCR. Bcl-2, Bax, and cleaved caspase-3 protein expression was assessed by Western blot. Results Compared with the control group, the survival rate of neuronal cells, the distribution of G1 phase cells, Bcl-2 mRNA and protein expression levels were decreased, and the distributions of S and G2 / M phase cells, the apoptosis rate, calcium ion level, Bax and cleaved caspase-3 protein expression levels were increased in the model group(P<0. 05). Compared with the model group, the neuronal cell survival rate, G1 phase cell distribution, snf Bcl-2 mRNA and protein expression levels were increased, whereas S and G2 / M phase cell distributions, apoptosis rate, calcium ion level, Bax and cleaved caspase-3 protein expression levels were decreased in the CCK-8 group(P<0. 05). Conclusions CCK-8 has an inhibitory effect on neuronal apoptosis induced by glutamate by inhibiting calcium influx and regulating Bax/ Bcl-2 expression in cells.