Multiple sclerosis (MS) is a degenerative autoimmune disease attacks the myelin sheath of the central nervous system (CNS) neurons causing different disabilities. According to recent evidence, the main bioactive component in Enicostema axillare, the Swrtiamarin (SM) has been found to exert anti-inflammatory and antioxidant activities against several diseases. However, SM activities in treatment of autoimmune diseases remain to be explored. Herein, we used a murine model of MS, to show that SM treatment ameliorates the severity of experimental autoimmune encephalomyelitis (EAE). This occurs through reducing the levels of pro-inflammatory cytokines and infiltration of CD4+CD45+ cells into CNS. That was associated with a reduction in the expression of STAT3 and NFkB in CD4+ T cells under Th17 and LPS-stimulated macrophages. Furthermore, in silico studies revealed that SM interacts with NF-E2-related factor 2 (NRF2), and therefore, suppressed oxidative stress by inducing formation NRF2-antioxidant response element (ARE) complex. We found that SM is an agonist of NRF2 complex regulating the total CD4 population and antioxidant markers in EAE mice. Molecular docking analysis showed a stable and higher binding affinity between SM and NRF2. Results revealed that SM treatment increased the complex formation between ARE and NRF2 where immunoprecipitation methods showed a higher binding affinity of ARE to NRF2 in SM treated animals. Complex formation triggered ARE cascade of antioxidant gene clusters and reduces the MS pathological alterations in EAE mice model. Current data proposed SM as an effective biomolecule in treatment of MS and controlling neuronal damage through inhibiting oxidative stress markers and targeting NRF2.