Background and objectives: Scrophularia megalantha is a native Iranian plant. In folk remedies, the species of the genus are used to treat stomach ulcers, goiter, eczema, cancer, psoriasis, and gall; however, there is not much research about S. megalantha. The current study aimed at evaluating the therapeutic effect of Scrophularia megalantha, a medicinal plant of Iran, on myelin oligodendrocyte glycoprotein 35-55 (MOG)-induced experimental autoimmune encephalomyelitis (EAE) as a model of multiple sclerosis (MS). Methods: The ethanol 80% extract of S. megalantha aerial parts was prepared by maceration method. The extract (100 mg/kg/day) was administered to C57BL/6 mice immunized with MOG (35-55) for 7 days, 3 weeks after EAE induction. The mice brain was removed and Hematoxylin-Eosin (H&E) was used to stain the sections. Moreover, spleen mononuclear cells from extract-treated or non-treated of EAE model mice were stimulated with MOG peptide and then culture supernatants were evaluated for IFN-ɣ, IL-17 and IL-10 cytokines using Enzyme-Linked Immuno Sorbent Assay (ELISA) kits. Results: Based on the obtained results, treatment with Scrophularia megalantha areal part extract significantly reduced inflammatory cells infiltration in the central nervous system (CNS) and also the disease severity in the experimental model of MS. Also, findings of the current study indicated that treatment with this medicinal plant in EAE mice model significantly decreased inflammatory cytokines including IFN-ɣ and IL-17 and vice versa significantly increased IL-10 as anti-inflammatory cytokine compared with non-treated of EAE model mice group. Conclusion: Scrophularia megalantha attenuated EAE by suppressing IFN-ɣ and IL-17 production and also increasing IL-10 cytokine. These findings suggested that this medicinal plant has the anti-inflammatory and immunomodulatory effects.