Multiple sclerosis（MS） is a systemic inflammatory illness of the central nervous system that involves demyelinating lesions in the myelin-rich white matter and pathology in the grey matter. Despite significant advancements in drug research for MS, the disease′s complex pathophysiology makes it difficult to treat the progressive forms of the disease. In this study,we identified a natural flavonoid compound icariin（ICA）as a potent effective agent for MS in ameliorating the deterioration of symptoms including the neurological deficit score and the body weight in a murine experimental autoimmune encephalomyelitis（EAE） model. These improvements were associated with decreased demyelination in the corpus callosum and neuron loss in the hippo-campus and cortex confirmed by immunohistochemistry analysis. Meanwhile, it was observed that the activation of microglia in cerebral cortex and hippocampus were inhibited followed by the neuroinflammatory cytokines downregulation such as IL-1β, IL-6 and TNF-α after ICA treatment, which was probably attributable to the suppression of microglial NLRP3 inflammasome activation.Additionally, molecular docking also revealed the binding force of ICA to NLRP3 inflammasome protein complexes in vitro. Taken together, our findings have demonstrated that ICA, as pleiotropic agent, prevents EAE-induced MS by improving demyelination and neuron loss, which interferes with the neuroinflammation via microglial NLRP3inflammasome activation.