Multiple Sclerosis (MS) disease and its related syndromes are initiated by a neurodegenerative process that occurs in the central nervous system with some autoimmunity component. The patients with MS syndrome lose their productivity because of long-term morbidity and need for special assistance in daily activities as well as the need for immunomodulatory treatments and multidisciplinary health care. The remyelination process in the central nervous system due to MS requires proliferation and differentiation of oligodendrocyte precursor cells to generate mature oligodendrocytes that have a capacity for migration and myelin production in the defected area. Remyelination process requires functional mitochondria that can produce sufficient levels of ATP molecules. This method requires high oxygen levels and therefore it generates high levels of destructive reactive oxygen species (ROS) which should be eliminated. A growing body of evidence has shown the crucial role of mitochondrial uncoupling proteins (UCPs) in reducing the production of ROS that leads to a reduction in the harmful effects of oxidative stress and subsequently attenuates neurodegenerative pathology. This review provides an overview of the critical role of oligodendrocyte and mitochondria in the progression of multiple sclerosis.