The aim of this study was determined the effects of Hesperidin (HP) on neuronal damage in brain tissue caused by Experimental allergic encephalomyelitis (EAE), an established model of multiple sclerosis in C57BL/J6 mice. To explore 40 mice were equally divided into four groups: (1) Control, (2) EAE, (3) HP, and (4) HP + EAE. 14 days after induction of EAE with MOG35-55 and pertussis toxin, the mice treated with HP at the doses of 50 mg/kg/day for 7 days subcutaneously. To our results HP treatment prevents the oxidative stress caused by EAE via a decrease in lipid peroxidations and increase in elements of the antioxidant defense systems in brain tissue. Also, EAE elevate the IL-17, express the pro-inflammatory cytokines, and caspase-3-like immunreactivity, show apoptosis, staining in EAE mice brain and increased the incidence of histopathological damage. However, immonohistochemical and histological changes were reversed with HP. Moreover, elevated TNF- and IL-1 levels, a result of EAE, were decreased in serum and neurological deficits as clinical signs were reversed with HP treatment in EAE mice, given HP. In conclusion, HP treatment effectively prevents oxidative, immunological and histological damage in the brain caused by EAE. It was thought that the beneficial effects of HP are likely a result of its strong antioxidant and anti-inflammatory properties.