Aim To observe the effect of Wnt/β-catenin signaling pathway on cerebral ischemia-reperfusion (CIR) injury by regulating the autophagy level of rat cortical neurons. Methods 56 male SD rats were randomly divided into 4 groups:sham operation group (Sham group), CIR group, Wnt/β-catenin agonist lithium chloride (LiCl) treatment group (LiCl＋CIR group), normal saline (NS) treatment group (NS＋CIR group), 14 rats in each group. Rat CIR damage model was established by middle cerebral artery occlusion with line embolus, with reperfusion 24 hours after ischemia 2 hours. Garcia neurological deficit score was used to evaluate the neurobehavioral changes of rats in each group.Cerebral infarction volume was measured by triphenyltetrazolium chloride staining. The expressions of β-catenin, LC3-Ⅱ and P62 proteins in rat cortex was detected by Western blot. Results After reperfusion for 24 h, compared with Sham group, the neurobehavioral score increased, the cerebral infarction volume increased, the cortical expression of β-catenin decreased, the cortical expression of LC3-Ⅱ increased, and the expression of P62 protein decreased in CIR group (P＜0.05). Compared with CIR group, the neurobehavioral score decreased, the cerebral infarction volume decreased, the cortical expression of β-catenin increased, the cortical expression of LC3-Ⅱ decreased, and the expression of P62 protein increased in LiCl＋CIR group (P＜0.05). Conclusion Wnt/β-catenin signaling pathway can improve the nerve injury by regulating autophagy in CIR rats.