Astrocytes (AST) play an important role in the pathogenesis of neurological disorders, and their activation is involved in the progression of multiple sclerosis (MS). (6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione (MASM), a novel derivative of matrine, exhibits vast pharmacological activities, such as anti-tumor, anti-fibrosis and immune regulation. In this study, we demonstrate that MASM is a promising agent for the treatment of experimental autoimmune encephalomyelitis (EAE). MASM not only inhibited inflammatory responses in LPS-stimulated astrocytes, but also suppressed the formation of reactive A1 astrocyte and maintained astrocytic functions, including the ability to promote synapse formation and phagocytose synapses and myelin debris. Importantly, MASM could significantly alleviate the development of EAE, with significant inhibition of inflammation, demyelination, axon loss and the body weight loss. Meanwhile, MASM also inhibited the activation of astrocytes and improved the function of BBB in vivo. These findings provide novel insights into the protective effect of MASM on EAE, which may be a promising drug candidate for treatment of EAE.