The abnormal amyloid-β accumulation is essential and obbligato in Alzheimer's disease pathogenesis and natural polyphenols exhibited great potential as amyloid aggregation inhibitors. However, the poor metabolic stability, low bioavailability, and weak blood-brain barrier crossing ability of natural polyphenol molecules fail to meet clinical needs. Here, we develop a universal protocol to prepare natural polyphenolic nanodots by heating in aqueous solution without unacceptable additives. The nanodots are able to not only inhibit amyloid-β fibrillization and trigger the fibrils disaggregation, but mitigate the amyloid-β plaques induced cascade impairments including normalizing oxidative microenvironment, altering microglial polarization, and rescuing neuronal death and synaptic loss, which resulting in significant improvements in recognition and cognition deficits in transgenic mice. More importantly, natural polyphenolic nanodots possess stronger anti-amyloidogenic performance compared with small molecule, as well as penetrate the blood-brain barrier. The excellent biocompatibility further guarantees the potential of natural polyphenolic nanodots for clinical applications. It is expected that natural polyphenolic nanodots provides an attractive paradigm to support the development of the therapeutics for Alzheimer's disease. This article is protected by copyright. All rights reserved.