To investigate the protective effect of whisker stimulation on barrel cortex ischemic stroke in mice and explore its mechanism. Methods: A total of 60 male C57BL/6 mice were randomly divided into the sham-operation group, ischemia group, and treatment group with 20 mice in each. The treatment group underwent establishment of the focal barrel cortex ischemia model, then 3 days later, received regular whisker stimulation (15 min/time, 3 times/day) for 12 days. At 3, 7, and 14 days after model establishment, the sticker removal test was performed in all 3 groups. At 14 days after model establishment, the HomeCage behavior test was performed; western blot was used to assess the expression levels of synaptophysin 1 (SYP-1), growth-associated protein 43 (GAP-43), brain-derived neurotrophic factor (BDNF), and neurofilament (NF) in the penumbral tissue; and immunofluorescent staining was applied to observe NF structure. Results: At 3, 7, and 14 days after ischemia model establishment, the ischemia group mice showed prolonged sticker contact time and removal time compared to the sham-operation group mice (all P<0.05). At 7 days after model establishment, the treatment group presented a shorter sticker removal time than the ischemia group (P<0.05); 14 days after model establishment, the treatment group showed both a shorter sticker contact time and shorter sticker removal time compared to the ischemia group (both P<0.05). The HomeCage test showed that the ischemia group and treatment group displayed a decrease in activity indicators and increase in immobility time compared to the sham-operation group (all P< 0.05); compared to the ischemia group, the treatment group showed significantly increased activity indicators and decreased immobility time (all P<0.05). Western blot showed that penumbral protein levels of BDNF, SYP-1 and GAP-43 were significantly increased 14 days after model establishment, and the increase was more pronounced in the treatment group (all P<0.05); the penumbral NF expression was significantly reduced, and regular whisker stimulation was able to reverse this change (P<0.05). Immunohistochemistry staining showed disorganized NF structure in the penumbra; while regular whisker stimulation significantly improved NF structural organization and led to stronger staining (P<0.05). Conclusion: Regular whisker stimulation improve the neurological deficits after focal barrel cortex ischemic stroke in mice, and part of its mechanism may be related to penumbral neuro- plasticity involving SYP-1, GAP-43, and NF.