Short-chain fatty acids (SCFAs), including butyrate, propionate, acetate, and valerate, produced by gut microbiota through dietary fiber fermentation, have immunomodulatory roles in multiple sclerosis (MS). SCFAs modulate inflammation and immune responses, particularly butyrate and propionate, which exhibit anti-inflammatory effects in both the gut and central nervous system (CNS). These SCFAs influence regulatory T lymphocytes and blood-brain barrier (BBB) permeability. The review discusses the potential therapeutic implications of SCFAs in MS, highlighting their ability to modulate the gut-brain axis and restore immune balance. Butyrate enhances BBB integrity and reduces inflammation by activating AMPK and modulating tight junctions. It also acts as a histone deacetylase (HDAC) inhibitor, promoting remyelination and Treg differentiation. Propionate modulates immune responses by activating GPCRs and reducing pro-inflammatory cytokines. Acetate and valerate also have immunomodulatory effects, with valerate showing potential in enhancing B lymphocyte suppression. SCFAs are involved in gut microbiota dysbiosis in MS, with altered SCFA levels linked to disease progression. The review emphasizes the importance of SCFAs in immune regulation and suggests future clinical trials to explore their therapeutic potential in MS.Short-chain fatty acids (SCFAs), including butyrate, propionate, acetate, and valerate, produced by gut microbiota through dietary fiber fermentation, have immunomodulatory roles in multiple sclerosis (MS). SCFAs modulate inflammation and immune responses, particularly butyrate and propionate, which exhibit anti-inflammatory effects in both the gut and central nervous system (CNS). These SCFAs influence regulatory T lymphocytes and blood-brain barrier (BBB) permeability. The review discusses the potential therapeutic implications of SCFAs in MS, highlighting their ability to modulate the gut-brain axis and restore immune balance. Butyrate enhances BBB integrity and reduces inflammation by activating AMPK and modulating tight junctions. It also acts as a histone deacetylase (HDAC) inhibitor, promoting remyelination and Treg differentiation. Propionate modulates immune responses by activating GPCRs and reducing pro-inflammatory cytokines. Acetate and valerate also have immunomodulatory effects, with valerate showing potential in enhancing B lymphocyte suppression. SCFAs are involved in gut microbiota dysbiosis in MS, with altered SCFA levels linked to disease progression. The review emphasizes the importance of SCFAs in immune regulation and suggests future clinical trials to explore their therapeutic potential in MS.