This study is to explore whether the Wnt/β-catenin signaling pathway is involved in the process of tripchlorolide (T₄) protecting against oligomeric Aβ₁₋₄₂-induced neuronal apoptosis.  Primary cultured cortical neurons were used for the experiments on day 6 or 7.  The oligomeric Aβ₁₋₄₂ (5 μmol·L⁻¹ for 24 h) was applied to induce neuronal apoptosis.  Prior to treatment with Aβ₁₋₄₂ for 24 h, the cultured neurons were pre-incubated with T₄ (2.5, 10, and 40 nmol·L⁻¹), Wnt3a (Wnt signaling agonists) and Dkk1 (inhibitors) for indicated      time.  Then the cell viability, neuronal apoptosis, and protein levels of Wnt, glycogen synthase kinase 3β (GSK3β), β-catenin and phospho-β-catenin were measured by MTT assay, TUNEL staining and Western blotting, respectively.  The result demonstrated that oligomeric Aβ₁₋₄₂ induced apoptotic neuronal cell death in a    time- and dose-dependent manner. Pretreatment with T₄ significantly increased the neuronal cell survival and  attenuated neuronal apoptosis.  Moreover, oligomeric Aβ₁₋₄₂-induced phosphorylation of β-catenin and GSK3β was markedly inhibited by T₄.  Additionally, T₄ stabilized cytoplasmic β-catenin.  These results indicate   that tripchlorolide protects against the neurotoxicity of Aβ by regulating Wnt/β-catenin signaling pathway.  This may provide insight into the clinical application of tripchlorolide to Alzheimer’s disease.