Abstract : Ischemic stroke has been ranked as the second cause of death in patients worldwide. Inflammation which is activated during cerebral ischemia/reperfusion is an important mechanism leading to brain injury. We aimed to investigate the effect of Berberine on cerebral ischemia/reperfusion injury and its effect to treat the inflammation. The study was carried out on 36 Wistar-albino rats, divided into four groups including: Sham group, ischemia/reperfusion group, ischemia/reperfusion + dimethyl sulfoxide and ischemia/reperfusion + Berberine 5 mg/kg injected intraperitoneally 1 hour before induction of ischemia. Measurement of brain tissue IL- 1β, ICAM- 1, caspase-3, Notch 1 and Jagged 1 was done after one hour of reperfusion in addition to assessment of the brain infracted area and histopathological analysis and the scoring of brain damage were determined. Berberine attenuates cerebral ischemia/reperfusion injury induced increase in IL-1β, ICAM-1 and caspase-3. The cerebral concentration of inflammatory parameter was significantly (*p<0.05) elevated in control group in comparison to sham group, while control and control- vehicle groups showed insignificant differences between them. Berberine treatment group was significantly (*p<0.05) lesser than control- vehicle group. Additionally, it reduces the size of infracted area and histopathological damage, such protective effect could be mediated by Notch 1 signaling pathway since The cerebral concentration of Notch 1 receptor was significantly (*p<0.05) elevated in control group in comparison to sham group, meanwhile control and control- vehicle groups showed insignificant differences between them. Berberine treatment showed significant further elevation in Notch 1 cerebral level in comparison with control-vehicle group. Berberine has a neurocytoprotective outcome against cerebral I/R injury which is manifested as anti-inflammatory anti-apoptotic effect that preserved cell structure and viability, which could be mediated by Notch 1 signaling pathway