Progressive pathology of Alzheimer's disease (AD) including aggregation of amyloid beta (Aβ) appears decades before the onset of dementia. Therefore, early intervention before the appearance of the symptoms is crucially important. We focused on food-derived hydrophilic amino acid ergothioneine (ERGO) because oral ERGO administration enhances cognitive function in normal mice. The purpose of the present study is to elucidate the preventive effect of ERGO on cognitive decline in the AD model, App^NL-G-F mice expressing humanized Aβ. App^NL-G-F mice were orally administered ERGO or vehicle weekly between 5 weeks to 7 months of age. Novel object and spatial recognition tests showed that ERGO administration significantly improved the cognitive declines in the App^NL-G-F mice. ERGO concentration in plasma of App^NL-G-F mice at 3 months of age reached a steady state around 10 µM, which was close to that reported in humans orally administered ERGO. Proteome analysis of the hippocampus samples showed that 71 and 91 proteins were significantly up- and down-regulated more than two-fold by ERGO treatment, respectively. Further enrichment analysis revealed that neurogenesis-related proteins were significantly enriched. Immunochemical analysis in the hippocampus showed that area of newborn neuron marker doublecortin-positive cells in the ERGO-treated App^NL-G-F mice was significantly higher than that in vehicle-treated mice. These results suggest that ERGO would prevent cognitive decline at least partially via the promotion of neurogenesis in App^NL-G-F mice.