Background Stroke is a collection of disorders that develop due to the rapid rupture of blood vessels in the brain or due to the blockage of blood flow. Ischemic stroke (IS) has high mortality as well as morbidity rates.Purpose The current work aimed to investigate the neuroprotective activities of pinobanksin against cerebral ischemic/reperfusion (C I/R) injury in a rat model through its anti-inflammatory properties.Methods Male Wistar albino rats underwent the middle cerebral artery occlusion (MCAO) method to initiate I/R injury. The experimental rats were orally treated with pinobanksin at various doses after 2 hours of MCAO operation. The infarct size, neurological score, edema and water content, and Evans blue assay were assessed. The inflammatory cytokines and biomarker (nuclear factor-kappa B (NF-kappa B), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2)) levels were studied using commercial kits. Histopathological analysis was performed on the brain tissues.Results The treatment with pinobanksin successfully mitigated the neurological deficits, edema and water content, infarct size, and Evans blue leakage in the C I/R-induced rats. The pro-inflammatory cytokine levels were reduced and interleukin-10 was increased by the pinobanksin in the I/R rats. The pinobanksin also effectively reduced NF-kappa B, PGE2, and COX-2 levels in I/R rats. The pinobanksin treatment effectively attenuated the brain histological alterations.Conclusion Altogether, this work highlighted the neuroprotective activity of pinobanksin in the C I/R injury in rats. The present findings could aid in the development of pinobanksin as a novel therapeutic intervention to prevent or reduce IS-induced brain injury.