ischaemic stroke accounts for almost 11% of all deaths worldwide and has a high incidence of permanent disability among patients. Baicalein has many beneficial pharmacological properties, including anti-inflammatory and anti-oxidant effects. However, the neuroprotective effect of baicalein is still unclear. The current study scrutinizes the neuroprotective effect of baicalein against the ischaemic/reperfusion (I/R) injury via alteration of the nuclear factor kappa B (NF-kB) and AMP-activated protein kinase/nuclear factor erythroid 2-related factor 2 AMPK/Nrf2 signaling pathway. Wistar rats were used for the current study. In rats, I/R injury was caused by transient occlusion of the middle cerebral artery for 1 h accompanied by reperfusion for 24 h. The rats were divided into different groups and treated with the different doses of baicalein (2.5, 5 and 10 mg/kg). The effects of baicalein on the murine neurological function were determined via infarct volume, neurological defect scores, and brain water content. The -inflammatory cytokines and oxidative stress were estimated in the region of the cortical along with the expression of apoptosis markers, such as B-cell lymphoma 2, Bax, and caspase-3. Quantitative reverse transcription polymerase chain reaction was used for the estimation of the NF-kB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression. Baicalein significantly (p < 0.001) ameliorated the infarction volume, brain water content, and neurological outcome, and the malondialdehyde level, and reduced the level of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, superoxide dismutase, glutathione, and catalase in a dose-dependent manner. Baicalein significantly (p < 0.001) altered the expression of COX-2, PGE2, LOX-1 and NF-kB as compared to I/R control group rats. Baicalein significantly reduced the Nrf2 and AMPK levels, and protected the rat brain against the I/R injury, suggesting a neuroprotective effect via down-regulation of NF-kB and LOX-1 expression and the AMPK/Nrf2 pathway.