Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination of the central nervous system (CNS). Optic neuritis (ON) is the most common symptom of MS, affecting 50% of patients; it can lead to apoptosis of retinal ganglion cells (RGCs) and possible blindness. Available immunomodulatory drugs can mitigate symptoms in subsets of patients but can be limited by severe adverse effects. Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we investigated the efficacy of two different metabolic interventions on motor and visual function: (1) dimethyl fumarate (DMF) and (2) a low-carbohydrate, high fat, fiber-enriched ketogenic diet (KD). DMF treatment significantly mitigated motor deficits in EAE mice but only modestly improved vision and RGC survival. Retrospective chart analysis revealed that >50% of patients discontinued DMF treatment but those that could tolerate the drug were largely protected from subsequent ON episodes after initiating treatment. The KD protected against the onset of EAE-induced optic neuritis and motor deficits and was efficacious when fed as a preventive regimen prior to EAE immunization as well as when initiated as an interventional regimen following the onset of EAE symptoms. This dietary strategy preserved oligodendrocytes and reduced infiltrating T cells and macrophages in the optic nerves. The KD also increased anti-inflammatory-associated omega-3 fatty acids in the plasma and reduced select cytokines in the circulation associated with inflammation and EAE pathologies. Together, these findings support that despite compliance challenges which each approach, DMF and a KD are effective metabolism-based therapies for mitigating autoimmuneinduced CNS sequelae.