Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) believed to be driven by autoimmune mechanisms. Genetic and environmental factors are implicated in MS development, and among the latter, diets and nutrients are emerging as potential critical contributors. However, a comprehensive understanding of their impacts and the underlying mechanisms involved is lacking. Harnessing state-of-the-art nutritional geometry analytical methods, it is first revealed that globally, increased carbohydrate supply is associated with increased MS disease burden, while fat supply has an opposite effect. Furthermore, in a MS mouse model, experimental autoimmune encephalomyelitis (EAE), it is found that an isocaloric diet high in carbohydrate aggravated EAE, while a diet enriched in fat (HF) is fully protective. This is reflected by reduced neuroinflammation and skewing toward anti-inflammatory phenotypes. The protective effects from the HF diet are multifaceted. Metabolically, HF increased lipid storage in immune cells, correlating with their increased anti-inflammatory IL-10 production. Transcriptionally and epigenetically, HF feeding preprogrammed naïve T cells toward a less activated but more tolerogenic phenotype. It is showcased that manipulating diets is a potentially efficient and cost-effective approach to prevent and/or ameliorate EAE. This exhibits translational potentials for prevention/intervention of MS and possibly other autoimmune diseases.