Significance Multiple sclerosis (MS) is the most common demyelinating disease in young adults. Advances in the understanding of the cellular mechanisms that contribute to MS may help to develop new therapies. Here, we elucidated the role of autophagy (a controlled intracellular pathway regulating the degradation of cellular components) and mitophagy (a specific form of autophagy that removes dysfunctional mitochondria) in MS. We found that human and experimental MS induces a mitochondrial deficit that leads to activation of autophagy and mitophagy. These phenomena play a causal role in MS because their inhibition with antipsychotic drugs prevents demyelination, induces remyelination, and reverts MS behavioral deficits. Our data suggest the repurposing of these Food and Drug Administration–approved drugs for the treatment of MS.