Schizophrenia is a serious psychiatric illness with an unclear cause. One theory is that demyelination of white matter is one of the main pathological factors involved in the development of schizophrenia. The current study evaluated the protective effects of Areca catechu nut extract (ANE) on a cuprizone-induced demyelination mouse model. Two doses of ANE (1% and 2%) were administered orally in the diet for 8 weeks. Animals subjected to demyelination showed impaired spatial memory and less social activity. In addition, mice subjected to demyelination displayed significant myelin damage in cortex and demonstrated a higher expression of NG2 and PDGFRα and AMPK activation. ANE treatment not only significantly enhanced cognitive ability and social activity, but also protected myelin against cuprizone toxicity by promoting oligodendrocyte precursor cell (OPC) differentiation. In addition, ANE treatment demonstrated significant dephosphorylation of AMPKα, indicating a regulatory role for ANE in schizophrenia. This study showed that ANE treatment may enhance cognitive ability and social activity by facilitating OPC differentiation and protecting against myelin damage in cortex. Results also suggest the AMPK signaling pathway may be involved in this process.