Capsaicin has been shown to exert neuroprotective effects. In this study, the effect of capsaicin in global cerebral ischaemia and reperfusion induced in the rat by transient occlusion of common carotid arteries was examined. Capsaicin was intraperitoneally (i.p.) given at doses of 1 or 2 mg/kg, 30 min prior to induction of brain ischaemia. The control group was treated with the vehicle. The lipid peroxidation biomarker malondialdehyde, nitric oxide and reduced glutathione brain levels were determined. Additionally, brain paraoxonase-1 activity, and the concentrations of glial fibrillary acidic protein, and interleukin-10 were measured and histopathological assessment of brain tissue damage was done. Results indicated that capsaicin significantly inhibited the ischaemia/reperfusion-induced increase in lipid peroxidation, nitric oxide and prevented the depletion of reduced glutathione. We further found that paraoxonase-1 activity and interleukin-10 concentration decreased significantly after ischaemia/reperfusion (I/R), which was prevented by treatment with capsaicin. Moreover, the increase in the level of glial fibrillary acidic protein induced by I/R was attenuated by capsaicin administration. The histopathological damage caused by ischaemia in cerebral cortex, hippocampus and substantia nigra was markedly improved by the higher dose of capsaicin. This suggests that capsaicin protects against the global ischaemia-induced neuronal damage by decreasing the level of oxidative stress and neuroinflammation.