BACKGROUND: Vagus nerve stimulation therapy is proven to produce neuroprotective effects against central nervous system diseases and reduce neurological injury, having a positive effect on the recovery of neurological functions in mouse model of stroke. OBJECTIVE: This study was aimed at exploring a wider time window for VNS treatment, investigating the long-term behavioral improvement of long-term VNS in mice after pMCAO, and exploring the antiapoptotic properties of VNS and its role in autophagy, all of which may be a permanent deficiency potential mechanism of neuroprotection in hemorrhagic stroke. METHODS: Permanent focal cerebral ischemia and implantation of vagus nerve stimulator were performed through intracavitary occlusion of the right middle cerebral artery (MCA). The vagus nerve stimulation group received five times vagus nerve stimulation from 6 h after surgery for 5 days. Adhesive removal test and NSS neurological score were used to evaluate the neurological deficit of mice. TTC staining of mouse brain tissue was performed one week after surgery in order to assess the area of cerebral infarction. Additionally, frozen sections were stained with Fluoro-Jade B to observe the apoptotic cells in the ischemic penumbra of brain tissue. Finally, Western blot was used to detect the changes in the levels of apoptosis-related proteins such as cleaved-caspase3 and Bcl-2 and autophagy-related proteins such as mTOR, Beclin-1, and LC3-II in brain tissue. RESULTS: VNS can effectively reduce the behavioral score of pMCAO mice; TTC results showed that VNS could effectively reduce the infarct area after pMCAO ( < 0.05). After VNS intervention of the pMCAO group compared with the pMCAO+VNI group, the FJB-positive cells in the VNS group were significantly decreased ( < 0.05); Western Blot analysis showed that the expression of cleaved-caspase3 in the brain tissue of mice increased after pMCAO ( < 0.05), and the expression of Bcl-2 decreased ( < 0.05). This change could be effectively reversed after VNS intervention ( < 0.05). CONCLUSION: VNS could effectively improve the behavioral performance of mice after permanent stroke in addition to significantly reducing the infarct size of the brain tissue. The mechanism may be related to the effective reduction of cell apoptosis and excessive autophagy after pMCAO by VNS.