Severe and persistent endoplasmic reticulum （ER） stress generates a distinct activation state in astrocytes, promoting the progression of Alzheimer’s disease (AD). The overactivation of astrocytes contributes to neuroinflammation and further loss of neuronal function. Therefore, modulating astrocytic activation is a potential neuroprotective approach. We have recently shown that artemisinin had significant neuroprotective effects. However, how artemisinin regulates astrocyte activation to improve AD processes remains to be explored. This study aimed to investigate the effect of artemisinin on astrocyte reactivity and its underlying mechanisms, like the regulation of ER stress. Our data show that amyloid β-peptide 1-42 (Aβ_1-42) induced ER stress and astrocyte reactivity in vitro and in vivo animal model 3×Tg-AD mice while artemisinin reversed the effect of Aβ_1-42. Artemisinin inhibits the release of inflammatory cytokines but promotes the expression of neurotrophic factors, thereby increasing astrocyte neurotropism to prevent neuronal injury. Artemisinin inhibits the phosphorylation of IRE1 and the downstream TRAF2-mediated nuclear factor-kappa B (NF-κB) signaling pathway. Importantly, the inhibitor of PP2A, which is a phosphatase of IRE1 reversed the effect of artemisinin on IRE1 phosphorylation and downstream signaling. Our results indicate that Artemisinin attenuated Aβ_1-42-induced astrocyte overactivation by inhibiting the IRE1/TRAF2 pathway. These findings suggest that artemisinin could be a potential drug for AD treatment.