Wingless-integrated/β-catenin (Wnt/β-catenin) signaling pathway plays a crucial role in the regulation of various processes including embryogenesis, organ development, injury repair, homeostasis and tissue remodeling. Upregulation or downregulation of this pathway is greatly implicated in different diseases such as liver and kidney diseases, lung fibrosis, osteoporosis, heart failure, vascular calcification, cellular senescence, neurodegenerative diseases and cancers. In brain, Wnt/β-catenin signaling is crucial for neuronal survival and neurogenesis, regulation of synaptic plasticity and blood-brain barrier integrity and function. Critically, Wnt/β-catenin signaling is highly suppressed in Alzheimer's disease (AD) brain. Moreover, loss of Wnt/β-catenin signaling is associated with amyloid-β production, hyperphosphorylation of tau protein in the brain and enhanced neuron susceptibility to Aβ-induced apoptosis, while its activation rescues Aβ-induced neuronal cell death and behavioral deficits. Moreover, it has been showed that Wnt/β-catenin signaling is crucial for synaptic plasticity that is associated with higher brain functions including memory and learning. Therefore, restoring Wnt/β-catenin signaling might be an interesting target for the rational design of novel therapeutic interventions in AD patients.