Alzheimer's disease (AD) is a well-known neurodegenerative brain disease, and no curative treatment has yet been developed. The main symptoms include various brain lesions, caused by amyloid β (Aβ) aggregation, and cognitive decline. Therefore, it is believed that substances that control Aβ will inhibit the onset of Alzheimer's disease and slow its progression. In this study, the effect of phyllodulcin, a major component of hydrangea, on Aβ aggregation and brain pathology in an animal model of AD was studied. Phyllodulcin inhibited the aggregation of Aβ and decomposed the pre-aggregated Aβ in a concentration-dependent manner. In addition, it inhibited the cytotoxicity of Aβ aggregates. Oral administration of phyllodulcin improved Aβ-induced memory impairments in normal mice, reduced Aβ deposition in the hippocampus, inhibited the activation of microglia and astrocytes, and improved synaptic plasticity in 5XFAD mice. These results suggest that phyllodulcin may be a candidate for the treatment of AD.