Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Riboflavin plays an important role in myelin formation, and its deficiency is implicated as a risk factor for multiple sclerosis. Here, we systematically reviewed the literature concerning the health benefits of riboflavin on MS. The literature recorded within four main databases, including relevant clinical trials, experimental, and case-control studies from 1976 to 2017 were considered. Both human and animal studies were included for review, with no restrictions on age, gender, or ethnicity.  Experimental studies demonstrated that riboflavin deficiency triggers neurologic abnormalities related to peripheral neuropathies such as demyelinating neuropathy. Moreover, randomized controlled trials (RCT) and case-control studies in which MS patients received riboflavin supplementation or had higher dietary riboflavin intake showed improvements in neurological motor disability. Riboflavin is a cofactor of xanthine oxidase and its deficiency exacerbates low uric acid caused by high copper levels, leading to myelin degeneration. The vitamin additionally plays a significant role in the normal functioning of glutathione reductase (GR) as an antioxidant enzyme, and conditions of riboflavin deficiency lead to oxidative damage. Riboflavin promotes the gene and protein levels of brain-derived neurotrophic factor (BDNF) in the CNS of an animal model of MS, suggesting that BDNF mediates the beneficial effect of riboflavin on neurological motor disability. Research to date generally supports the role of riboflavin in MS outcomes. However, further observational and interventional studies on human populations are warranted to validate the effects of riboflavin.