Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive learning and cognitive damage. Several hypotheses such as amyloid cascade hypothesis, hyper-phosphorylated τ hypothesis, and energy metabolism hypothesis have been proposed to elucidate the disease. However, the exact mechanism of AD remains unclear and current therapeutic strategies are miserable. Cumulative evidence showed that neuroinflammation plays a significant role in the pathogenesis of the AD. Oxymatrine (OMT), a plant-derived bioactive compound, has anti-viral, anti-fibrosis, and anti-tumor effects through the involvement of several immune-related signaling pathways. Whether OMT can attenuate the pathology of AD is largely unknown. In this manuscript, we found that treatment of OMT can significantly improve cognitive and learning abilities of AD mice during various behavioral test. Treatment of OMT can significantly reduce the densities of Aβ plaques and astrocyte clusters in the neocortex and hippocampus of AD mice. Furthermore, treatment of OMT significantly reduced the concentration of pro-inflammatory cytokines including IL-6, IL-1β, TNF-α and IL-17A in AD mice. Taken together, our data indicate that OMT may serve as a potential drug for AD.