Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease. Therapy for MS does not always slow down the progression of the disease. In many cases, pathogenetic therapy of MS leads to serious side-effects, in particular, to immunosuppression, limiting using of various disease modifying therapy (DMT) in MS. In this regard, it is important to study the potential use of drugs that have immunomodulatory and neuroprotective effects, as well as a favorable safety profile. Polyphenols (compounds containing phenolic and hydroxyl groups, often of natural origin) have the ability to modulate immunoregulatory targets, reducing the production of various pro-inflammatory cytokines that play an important role in the pathogenesis of MS. The combined use of DMT and substances with a favorable safety profile, anti-inflammatory activity, and the ability to penetrate the blood-brain barrier, such as polyphenols, may be one of the promising strategies in the treatment of MS to improve the quality of life of patients. In this review, we consider the mechanisms of action of polyphenols in MS, their application in experimental models of MS, and the results of clinical studies of polyphenols in MS.