Background <p>In multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE), cellular inflammation and oxidative stress play key roles in disease pathogenesis. Melatonin and curcumin are natural compounds recognized for their neuroprotective properties. This study investigated their combined therapeutic potential in the EAE model.</p> Methods <p> Thirty female C57BL/6 mice were immunized with the MOG^35–55 peptide to induce disease. Starting at 10 days post-immunization, mice received vehicle, melatonin, curcumin, or a combined treatment. Leukocyte infiltration and demyelination were assessed by hematoxylin–eosin and Luxol Fast Blue staining, respectively, glial cell density was analyzed via immunohistochemistry, serum pro-inflammatory and anti-inflammatory biomarkers were measured by enzyme-linked immunosorbent assay (ELISA), and expression of oxidative stress-related genes was quantified by real-time RT-PCR.</p> Results <p> All treatment groups exhibited reduced clinical severity and less leukocyte infiltration compared to untreated mice. The combined melatonin and curcumin therapy, however, produced superior outcomes. It significantly attenuated demyelination and promoted remyelination more effectively than single-agent treatments. This combination also resulted in the greatest reduction in blood–brain barrier permeability and the most substantial decrease in activated astrocytes and microglia. At the molecular level, the combined treatment significantly downregulated the pro-oxidant gene synthase while potently upregulating key antioxidant genes.</p> Conclusion <p> The combined treatment of melatonin and curcumin significantly improved neurological function, reduced inflammation and oxidative stress, and enhanced remyelination in EAE mice. These findings suggest the therapeutic potential of these complementary agents, acting through a number of different pathophysiological pathways relevant to MS.</p>