Abstract Background Multiple sclerosis (MS), an autoimmune and degenerative disease, is characterized by demyelination and chronic neuroinflammation.Bixin is a carotenoid isolated from the seeds of Bixa orellana that exhibits various potent pharmacological activities, including antioxidant, anti-inflammation, and anti-tumor. However, the effects of bixin on MS remain elusive.Methods To evaluate the effects and underlying molecular mechanisms of bixin on MS, experimental autoimmune encephalomyelitis (EAE) was established in C57BL/6 mice, which were treated with intragastric administration of bixin solutions. To evaluate the molecular mechanisms of bixin, quantitative reverse-transcription PCR, western blot, immunohistochemistry, and enzyme-linked immunosorbent assay analyses were performed.Results We found that bixin significantly improved the symptoms in EAE mice, and suppressed microglia aggregation and TXNIP/NLRP3 inflammasome activity by scavenging excessive reactive oxygen species (ROS). Furthermore, bixin activated nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genes in EAE mice, and these effects were suppressed upon inhibiting Nrf2 expression with the Nrf2 inhibitor ML385.Conclusions Bixin prevented neuroinflammation and demyelination in EAE mice mainly by scavenging ROS through activation of the Nrf2 signaling pathway. Taken together, our results indicate that bixin is a promising therapeutic candidate to treat MS.