AbstractAlzheimer's disease (AD) is a common form of neurodegenerative disease in the elderly. Amyloid‐β(Aβ)‐associated neurotoxicity is an important component of the neurodegenerative change in AD. Recent studies have revealed a beneficial effect of anthocyanins in improving learning and memory in AD animal models. Using cultured HT22 mouse hippocampal neuronal cells as an in vitro model, we examined in this study the protective effect of ten pure components of anthocyanins against Aβ42‐induced cytotoxicity and also investigated the mechanism of their protective effects. We found that treatment of HT22 cells with the pure components of anthocyanins dose‐dependently rescued Aβ42‐induced cytotoxicity, with slightly different potencies. Using petunidin as a representative compound, we found that it enhanced mitochondrial homeostasis and function in Aβ42‐treated HT22 cells. Mechanistically, petunidin facilitatedβ‐catenin nuclear translocation and enhanced the interaction betweenβ‐catenin and TCF7, which subsequently upregulated mitochondrial homeostasis‐related protein Mfn2, thereby promoting restoration of mitochondrial homeostasis and function in Aβ42‐treated HT22 cells. Together, these results reveal that the pure components of anthocyanins have a strong protective effect in HT22 cells against Aβ42‐induced cytotoxicity by ameliorating mitochondrial homeostasis and function in aβ‐catenin/TCF‐dependent manner.