Artesunate is a semi-synthetic derivative of artemisinin that is used in the treatment of patients with malaria. Artesunate has also been reported to exert immune-regulatory, antitumor, hepatoprotective, anti-inflammatory and smooth muscle relaxing functions. The present study aimed to investigate the putative protective effects of artesunate against cerebral ischemia/reperfusion injury (CIRI), and to elucidate the molecular mechanisms underlying its effects. A CIRI mouse model was created via middle cerebral artery occlusion for 2 h, followed by 22 h of reperfusion. Mice were treated with 10-40 mg/kg artesunate. The present results demonstrated that treatment with artesunate significantly reduced the cerebral infarct volume and potentiated the recovery of neurological function in CIRI mice. Oxidative stress and inflammation markers were revealed to be significantly downregulated following treatment with artesunate in CIRI mice. Furthermore, artesunate was demonstrated to activate nuclear factor erythroid 2-related factor 2 (Nrf2), inhibit caspase-3 activity, reduce the apoptosis regulator BAX/apoptosis regulator Bcl-2 expression ratio and suppress the phosphorylation of the mitogen-activated protein kinase (MAPK) p38 in CIRI mice. In conclusion, the present findings suggested that artesunate may exert protective effects against CIRI through the suppression of oxidative and inflammatory processes, via activating Nrf2 and downregulating ROS-dependent p38 MAPK in mice.