The present study has been explored the neuroprotective efficacy of myricitrin and unveil the mechanism of action via the regulation of Nrf2/ HO-1/ARE-dependent signaling cascade in hypoxic-ischemic (HI) induced brain injury of neonatal rats. Upon HI operation neonatal rats received 20 and 40mg/kg bw of myricitrin as intraperitoneally up to one week twice in a day. Myricitrin administration augmented HI induced increase of infarct volume and oedema of the brain, as well as improve neurobehavioral impairments. Further, we measured the level the antioxidant enzymes and oxidative stress marker level of ROS, NO and product of lipid peroxidation. These data support the well-established radical scavenging and antioxidant potential of myricitrin corresponds to a significant decline in most vulnerable radical formation with an obvious increase in antioxidant enzyme content. Interestingly, myricitrin source a significant reduction in NF-κB p65 and inflammatory marker gene expression, while reducing levels of the nuclear fraction of Nrf2- antioxidant response element (ARE) and cytosolic fraction of HO-1 enzyme activation. The results substantiate the efficiency of myricitrin an activation of Nrf2/ARE-dependent HO-1 pathway via improve defense mechanism and mitigate oxidative stress associated neuroprotective effect