Ferroptosis, a form of cell death characterized by lipid peroxidation, has been shown to play an essential role in neuronal death. Artemisinin, a first-line antimalarial drug, is neuroprotective, but its effect and underlying mechanisms on ferroptosis are unknown. The present study found, for the first time, that Artemisinin concentration-dependently protected against cell death and prevented neuronal lipid peroxidation induced by erastin in HT22 and SY5Y with a similar effect to the positive control ferrostatin-1. Mechanistically, Artemisinin increases the expression of the SLC7A11 and GPX4, while knocking out these two proteins inhibits the effect of Artemisinin, indicating the effect of Artemisinin is mediated, at least in part, by the SLC7A11 and/or GPX4 relative pathways. Artemisinin stimulated the phosphorylation of AMPK and its downstream target NRF2. Inhibition of NRF2 partially blocked the effect of Artemisinin. Further experiments showed that the effect of Artemisinin on GPX4 is NRF2 dependent, while that of SLC7A11 is NRF2 independent. Interestingly, Molecular Docking and SPR assay showed that Artemisinin is directly bound to SLC7A11 at cysteine residues and glutamate residues in SLC7A11, suggesting the direct interactions of Artemisinin and SLC7A11 involved. In vivo, Artemisinin inhibited ferroptosis induced by intrahippocampal injection of imidazole-ketone-erastin (IKE) verified the anti-ferroptosis of Artemisinin. Moreover, Artemisinin reversed Aβ1-42-induced cell death (which we have also verified as ferroptosis), lipid peroxidation and glutathione depletion in HT22 cells, primary hippocampal neurons, and 3xTg mice via the SLC7A11/GPX4 pathway. These results demonstrate that Artemisinin can inhibit neuronal ferroptosis induced by different ferroptosis inducers by activating the SLC7A11/GPX4 relative pathways in vitro and in vivo. Our findings support that ferroptosis is a novel mechanism for neuroprotection of Artemisinin and that targeting the SLC7A11/GPX4 relative pathways is a promising approach to ameliorate neurodegenerative diseases like Alzheimer's Disease (AD).