Background: Cerebral injury is a common health crisis that may affect the patient lifestyle or cause death. Although many drugs involved in the treatment of such cases and relieving symptoms, there is no precise cure. Accordingly, the importance of protection against the insult could be understood, especially when natural products can be a part of the protective agent. Objectives: The target of the current study was to inspect the pharmacological actions of sandalwood essential oil (SEO) through oxidative stress as well as inflammation pathways in mice exposed to middle cerebral artery occlusion (MCAO) surgery as a reproducible mean to generate focal brain ischemia. Materials and Methods: Ischemic animals were treated with sandalwood oil and were compared to cerbrolysin actions, atypical neuroprotective medication. Infarct volume, measured via sliver staining, as well as several behavioral tests including neurological deficits scores was measured to evaluate sandalwood oil defensive effects. Neural degeneration, measured via Fluoro-Jade B staining, levels of different inflammatory mediators including interleukin (IL)-1 β, IL-6, tumor necrosis factor-α, and nuclear factor-kappa β, and antioxidants enzymes activities containing glutathione, superoxide dismutase, and catalase swere assessed. Results: Sandalwood oil exposure improved the neurological deficits as well as behavioral experiments and diminished infarct volume and neural degeneration in ischemic mice. In addition, oxidative stress overproduction and inflammation cascade were significantly suppressed subsequent to SEO treatment. Conclusion: These results suggest that sandalwood oil abstains protective effects through deterring oxidative stress and inflammation cascade in cerebral ischemia.