Multiple sclerosis is an organ-specific autoimmune disease that targets the myelin antigen in the central nervous system. Nobiletin is a dietary polymethoxylated flavonoid found in citrus fruits. In this study, we investigated how nobiletin affects the disease state and immune responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis mice. Nobiletin was administered orally from 14 days before immunization until the end of the experiment, and clinical scores were determined. The production levels of interleukin-17A and interferon-γ were measured in a culture supernatant of splenocytes stimulated with myelin oligodendrocyte glycoprotein. In addition, flow cytometric analysis was performed to examine the effect of nobiletin on T cell differentiation in vitro. Admin-istration of nobiletin significantly decreased the clinical score and interleukin-17A production in splenocytes. Furthermore, in vitro analysis showed that nobiletin significantly suppressed Th17 cell differentiation and interleukin-17A production in a dose-dependent manner. The results suggest that nobiletin attenuates experimental autoimmune encephalomyelitis severity through modulation of Th17 cell differentiation.