The pathogenesis of Alzheimer’s disease is not known at present but toxicity of amyloid-beta peptide (Aβ) is one of the central hypotheses. Aβ can promote excitotoxicity by interacting with oxidative stress, mitochondrial dysfunction and neuroinflammation. So far, no effective method which can specifically treat AD, suggesting that the development of more effective therapies against AD is crucial. In this present study, we found that artemisinin, a first line antimalarial drug used in clinic for decades, improved the cognitive deficit and other AD-type pathologies in aged Alzheimer’s disease animal model 3xTg-AD mice. Artemisinin dose-dependently reduced the cell injury and improved neuroinflammation while decreased amyloid-beta deposit and hyperphosphorylation of tau protein in aged 3xTg-AD mouse brain. Artemisinin also inhibited glia cell activation, inflammation and nec-apoptosis. Western blot studies showed that artemisinin stimulated the activation of ERK/CREB/BDNF pathway. Consistent with this hypothesis, artemisinin concentration-dependently promoted the survival of SH-SY5Y cell line against toxicity of amyloid-beta protein 1-42 induced ROS accumulation, caspase activation, LDH release and apoptosis. Artemisinin also stimulated the phosphorylation of ERK, CREB in SH-SY5Y cells in time and concentration-dependent manner. Inhibition of ERK/CREB/BDNF pathway attenuated the protective effect of artemisinin. Taken together these result suggested that artemisinin has the potential to protect neuronal cells in vitro as well as in vivo animal model 3xTg-AD mouse via, at least in part, the activation of the ERK/CREB/BDNF pathway. Our findings also strongly support the potential of artemisinin as a new multi-target drug that can be used for preventing and treating the Alzheimer’s disease.