Alzheimer's disease (AD) is a progressive neurodegenerative disorder correlated with age, characterized by the accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles. The mammalian target of rapamycin (mTOR) is an important protein that regulates Aβ clearance and tau phosphorylation. Therefore, mTOR has become a pivotal therapeutic target for AD treatment. In this study, we discovered a natural product, glaucocalyxin A (GLA), as a new mTOR inhibitor based on a high-throughput screening platform with α-screen technology against our natural product library. Further study showed that GLA increased Aβ clearance involving the protein kinase B/mTOR/autophagy signaling pathway and inhibited tau phosphorylation involving the mTOR/70-kDa ribosomal protein S6 kinase pathway, which highlighted the therapeutic potential of GLA for the AD treatment.