Alzheimer’s disease (AD) is a prevalent age-related neurodegenerative disorder caused by a multifactorial etiology, thus dietary intervention plays an important role in the prevention of AD at its early stage. Selenium (Se)-enriched green tea (Se-GT) exhibits benefits for reducing the risk of several diseases. However, few studies were reported on Se-GT in the intervention of AD and its associated mechanism. The current study was designed to investigate the Se-enriched green tea water extract (Se-TE) on the pathologies of triple transgenic AD mice and primary neurons, as well as its potential regulatory mechanism. Our results indicated that Se-TE supplement ameliorated learning and memory impairment of AD mice, and exerted neuroprotective effects, evidenced as by inhibiting β-amyloid generation via regulating the expression of insulin-degrading enzyme and proliferator-activated receptor γ reducing tau hyperphosphorylation via regulating glycogen synthase kinase 3β and protein phosphatase 2A, repairing neuronal injury and reducing neuronal apoptosis via inhibiting endoplasmic reticulum stress and oxidative stress. Our research findings illuminate the advantageous effects of Se-TE in both the prevention and alleviation of AD.