In addition to cognitive impairments, deficits in non-cognitive behaviors are also common neurological sequelae in Alzheimer's disease and its animal models. Hesperidin, a flavanone glycoside found abundantly in citrus fruits, was orally given (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, a mouse model of cerebral amyloidosis for Alzheimer's disease. After a relatively short-term treatment of 10 days, hesperidin significantly restored deficits in non-cognitive nesting ability and social interaction. Further immunohistochemical analysis showed significantly attenuated β-amyloid deposition, plaque associated APP expression, microglial activation and TGF-β immunoreactivity in brains of APP/PS1 mice, which suggests that ameliorated behavioral impairments might be attributable to reduced Aβ deposition and attenuated neuro-inflammatory reaction. Additionally, efficient anti-inflammatory effects of hesperidin were confirmed in vitro. Our findings suggest that hesperidin might be a potential candidate for the treatment of AD or even other neurodegenerative diseases.