Ischemic stroke is one of the leading causes of death and disability of adults at present. Despite the costs of the disease are expected to reach 240.67 billion dollars by 2030, options for treatment against ischemic stroke are still very limited. Current therapies have failed to reduce neuronal injury, neurological deficits, and mortality rates except for anti-thrombolytics and hypothermia treatment, which suggests that development of novel therapies against ischemic stroke are urgently needed. In our study, we found that artemether, used as anti-malarial clinically, improved the neurological deficits, attenuated the infraction volume and brain water content in a middle cerebral artery occlusion (MCAO) animal model. Furthermore, artemether treatment significantly suppressed cell apoptosis, promoted cell proliferation and promoted the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and cAMP responsive element-binding protein (CREB). Moreover, PD98059, a ERK1/2 inhibitor, relieved the protective effect of artemether after ischemic stroke. Similarly, in oxygen-glucose deprivation/ reperfusion (OGD/RP) cell models, pretreatment with artemether induced the suppression the intracellular ROS; the down-regulation of LDH activity; the reduction of caspase 3 activity and of the apoptosis cell rate and reversed the decrease of mitochondrial membrane potential. Similarly, artemether promoted the activation of Erk1/2-P90rsk-CREB signaling pathway and this effect was blocked by the inhibition or knockdown of ERK1/2. Therefore, our study is aimed to study the neuroprotective effect of artemether on ischemic stroke, which may provide essential evidence for finding new therapeutic candidate for the prevention and treatment of ischemic stroke.