Alzheimer disease (AD) is a neurodegenerative disorder associated with age which represents the most common cause of dementia. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairments in various animal models for cognitive deficits, including senescence-accelerated mouse prone 8. Triple transgenic (3ΧTg) AD mouse model develops amyloid beta (Aβ) and tau pathologies in a progressive manner, with a specific temporal and anatomic profile mimicking the pattern that takes place in the human brain with AD, and shows cognitive alterations characteristic of the disease. In the present study, we examined the effects of nobiletin on cognitive impairment and Aβ levels in 3ΧTg AD mice. 3ΧTg AD male mice (6 months of age) were intraperitoneally administered 10 or 30 mg/kg nobiletin for 3 months and subjected to behavioral analyses. Treatment of 3ΧTg AD mice with 30 mg/kg nobiletin ameliorated the impairment of working memory and recognition memory without affecting number of arm entries and total exploration time in Y-maze and novel object recognition test, respectively. Nobiletin also restored the increase in the soluble Aβ_1-40 level in the brain of 3ΧTg AD mice in a dose-dependent manner. Together, the markedly beneficial effects of nobiletin represent a potentially useful treatment for ameliorating the cognitive deficits and accumulation of soluble Aβ_1-40 in AD.