Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that inflammation, demyelination, oligodendrocyte loss, gliosis, axonal injury and neurodegeneration are the main histopathological hallmarks of the disease. Although MS was classically thought as a demyelinating disease, but axonal injury occurs commonly in acute inflammatory lesions. In MS microglial activation is not only responsible for inflammatory cascade but also creates degenerative cascade. The evidence has shown mitochondrial dysfunction plays an important role in axonal degeneration in all stages of MS due to neuronal cell loss and activation pro-inflammatory cytokines. Neuronal loss occurs as a result of apoptosis and necrosis and mitochondrial pathway is the main important system for apoptosis and this way was involved in neurodegenerative disorders such as MS. Hence in multiple sclerosis, mitochondrial dysfunction causes energy failure and then increases inflammation and demyelination in neurons.