<p>Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system. In this disease, mitochondrial dysfunction contributes to neurodegeneration, axonal loss, and progressive disability. Extracellular vesicle (EV)-mediated mitochondrial transfer has emerged as a promising cell-free strategy to restore mitochondrial homeostasis and modulate immune responses within the CNS. Preclinical studies, particularly in experimental autoimmune encephalomyelitis models, demonstrate that EV-based delivery of mitochondrial cargo improves cellular bioenergetics. In parallel, this approach reduces oxidative stress and neuroinflammation while supporting remyelination and neuroprotection. This review summarizes the mechanistic rationale, current preclinical evidence, and future translational perspectives of EV-mediated mitochondrial therapy in MS.</p> Graphical Abstract <p></p> <p>Schematic illustration showing the dual role of neuronal–microglial interaction under pathological and therapeutic conditions. (Left) Neuronal injury caused by oxidative stress, reduced ATP production, and reactive oxygen species (ROS) results in mitochondrial damage and the release of mtDNA, which is taken up by microglia, leading to microglial activation and neuroinflammation. (Right) Under therapeutic conditions, extracellular vesicle (EV)-mediated transfer of mitochondrial components or protective factors restores mitochondrial function, reduces neuroinflammation, and promotes neuronal recovery</p>