Oxidative stress is one of the main causes of neurodegenerative diseases such as Alzheimer's disease (AD), which eventually becomes a heavy economic and social burden as the aged population increases without effective treatment. Here, we found that artemisinin, an anti-malarial Chinese medicine, have the neuroprotective effects. However, the antioxidative effect of artemisinin and its potential mechanisms remain to be elucidated. In this study, we found that artemisinin improved SH-SY5Y and hippocampal neuronal cells from H2O2-induced cell death at clinically relevant doses in a concentration-dependent manner. Further studies have shown that artemisinin can significantly restore nuclear morphology, improve abnormal changes in intracellular ROS, significantly reduce mitochondrial membrane potential, and restore nuclear morphology and caspase-3 activation, thereby improving H2O2-induced neuronal cell death. Flow cytometry showed that artemisinin significantly reduced the apoptosis of SH-SY5Y cells exposed to H2O2. Furthermore, Western blot analysis showed that artemisinin stimulated the phosphorylation and activation of AMP-activated protein kinase (AMPK) in SH-SY5Y cells in a time- and concentration-dependent manner, while the application of AMPK inhibitor Compound C or decrease the expression of AMPKα using shRNA blocked the protective effect of artemisinin. Similar results were obtained in primary cultured hippocampal neurons. Taken together, these results indicated that artemisinin can protect neuronal cells from oxidative damage through the activation of AMPK. Because artemisinin can easily cross the blood-brain barrier with few side effects, our findings support that artemisinin is a potential drug for neurodegenerative diseases.