Artemisinin is a clinically safe and potent anti-malarial drug that possess the most rapid action of all the currently available drugs against plasmodium falciparum malaria. At present, we found that artemisinin protected different neuronal cells such as PC12 cells, SH-SYSY cells and primary cultured neurons from oxidative stress-induced cell damage. For instance, artemisinin pretreatment significantly attenuated H2O2/ SNP/Aβ-induced cell damage in PC12 cells, and this protective effect was attributed to reduced intracellular reactive oxygen species (ROS) production, LDH release, caspase 3/7 activities, cell apoptosis and the maintenance of mitochondrial membrane potential. Western blot analysis showed that artemisinin induced the phosphorylation of ERK, AMPK and CREB, but not AKT. Moreover, the protective effect of artemisinin was abolished by knocking down ERK and AMPK by siRNA or blocking these signaling pathway by specific inhibitors PD98059 and Compound C, whereas the PI3K inhibitor LY294002 had no effect. These results suggested that artemisinin confers neuroprotective effects by suppressing oxidative stress induced cell damage via the activation of ERK/AMPK signaling. In addition, our current data showed that artemisinin improved the cognitive deficit of AD mice. These results support that artemisinin could be potentially used for preventing neuronal degenerative disorders like Alzheimer’s disease.