Bioflavonoids are being utilised as neuroprotectants in the treatment of various neurological disorders, including Alzheimer’s disease (AD). Astilbin, a bioflavanoid, has been reported to have potent neuroprotective effects, but its preventive effects on amyloid-β (Aβ)-induced, Alzheimer’s disease-related, cognitive impairment, and the underlying mechanisms of these effects have not been well characterised. Five-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group and two astilbin (either 20 or 40 mg/kg per day, intraperitoneally) groups. After 8 weeks of treatment, they observed beneficial effects of astilbin (40 mg/kg per day), including lessening learning and memory deficits and reducing plaque burden and Aβ levels. Furthermore, the expressions of both the cAMP responsive element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly increased and the disturbance of AKT/GSK-3b signalling pathway was markedly ameliorated in the hippocampus of astilbin-treated (40 mg/kg per day) group. These data suggest that astilbin might be a potential therapeutic agent against AD.