Ginkgolide B (GB), a diterpenoid lactone compound derived from Ginkgo biloba extract, exhibits anti-inflammatory and inhibits neuroexcitotoxicity. However, its specific pharmacological effects and mechanisms in Alzheimer's disease (AD) treatment remains unexplored. The study aimed to investigate the positive therapeutic effect of GB under clinical equivalent doses on the improvement of memory deficit in the APP/PS1 mice, and further explore the potential mechanism. The 8-month old APP/PS1 mice were used as an AD model, with or without gavagely administered GB for two months. The therapeutic effects were characterized by various ethological experiment and pathomorphism observatione; The underlying mechanisms were revealed by chromatin immunoprecipitation and were verified in the primary hippocampal neurons. We found that GB significantly alleivated memory impairments and reduced Aβ deposition in APP/PS1 mice. This effect was linked to the decreased phosphorylation of APP at Thr668, while APP and PS1 levels remained unchanged. GB restored mitochondrial biogenesis deficits and improved mitochondrial dysfunction. HADC6-mediated H4K5 acetylation upregulated the expression of GluN2B and pgc-1α promoter in GB-treated APP/PS1 mice. Finally, inhibition of HDAC6 mitigated Aβ-induced damage in primary neurons. This study suggested that GB ameliorated the cognitive impairment of the APP/PS1 mice by the HDAC6/H4K5/Glun2B and HDAC6/H4K5/PGC-1α pathway.