Objective To investigate the effects of vagus nerve electrostimulation (VNS) on the brain damage of rat middle cerebral artery occlusion (MCAO)/reperfusion model and its mechanism. Methods Twenty four adult male SD rats were randomly divided into two groups (12 each): MCAO/reperfusion group (MCAO group) and MCAO/reperfusion+VNS group (MCAO+VNS group). Subsequently, the neurological function deficit was determined by neurological scoring according to Zea Long scoring method 24h after MCAO/reperfusion. The cerebral infarction volume was determined by TTC assay. The cell apoptosis in brain damage zone was determined by TUNEL assay. Then, the effect of VNS on cAMP response element binding protein (CREB) and p-CREB protein expression was determined by Western blotting. The effect of VNS on Bcl-2 and Bax expression was determined by immunohistochemistry assay. Results Compared with MCAO group, VNS significantly inhibited MCAO-induced neurological deficit (P<0.01), decreased brain infarct volume (P<0.01) and cell apoptosis (P<0.01), increased the expression of p-CREB protein (P<0.01) and the number of Bcl-2-position cells (P<0.01) together with decreasing the number of Bax-position cells (P<0.01). However, VNS did not affect the expression of CREB protein (P>0.05). Conclusion VNS may ameliorate MCAO-induced neurological deficit and decrease brain infarct volume, which may be related to the promotion of p-CREB protein expression level.