Epigenetic changes are involved in learning and memory, and histone deacetylase (HDAC) inhibitors are considered potential therapeutic agents for Alzheimer's disease (AD). We previously reported that (-)-epigallocatechin-3-gallate (EGCG) acts as an HDAC inhibitor. Here, we demonstrate that EGCG reduced β-amyloid (Aβ) accumulation in vitro and rescued cognitive deterioration in senescence-accelerated mice P8 (SAMP8) via intragastric administration of low- and high-dose EGCG (5 and 15 mg/kg, respectively) for 60 days. The AD brain has decreased levels of the rate-limiting degradation enzyme of Aβ, neprilysin (NEP). We found an association between EGCG-induced reduction in Aβ accumulation and elevated NEP expression. Further, NEP silencing prevented the EGCG-induced Aβ downregulation. Our findings suggest that EGCG might be effective for treating AD.