The marine natural product fucoxanthin has been reported previously to produce anti-Alzheimer's disease (AD) neuroprotective effects in vitro and in vivo. Fucoxanthin was also demonstrated to be safe in preclinical and small population clinical studies, but the low bioavailability of fucoxanthin in the central nervous system (CNS) has limited its clinical applications. To overcome this, poly lactic--glycolic acid--polyethylene glycol loaded fucoxanthin (PLGA-PEG-Fuc) nanoparticles with diameter at around 200 nm and negative charge were synthesized and suggested to penetrate into the CNS. Loaded fucoxanthin could be liberated from PLGA-PEG nanoparticles by sustained released in the physiological environment. PLGA-PEG-Fuc nanoparticles were shown to significantly inhibit the formation of Aβ fibrils and oligomers. Moreover, these nanoparticles were taken up by both neurons and microglia, leading to the reduction of Aβ oligomers-induced neurotoxicity in vitro. Most importantly, intravenous injection of PLGA-PEG-Fuc nanoparticles prevented cognitive impairments in Aβ oligomers-induced AD mice with greater efficacy than free fucoxanthin, possibly via acting on Nrf2 and NF-κB signaling pathways. These results altogether suggest that PLGA-PEG nanoparticles can enhance the bioavailability of fucoxanthin and potentiate its efficacy for the treatment of AD, thus potentially enabling its future use for AD therapy.