Chronic fatigue syndrome (CFS) is a pathological state of extreme tiredness that lasts more than six months and may possess an impact on the social, emotional, or occupational functioning of an individual. CFS is characterized by profound disabling fatigue associated with infectious, rheumatological, and neurological symptoms. The current pharmacological treatment for CFS does not offer a complete cure for the disease, and none of the available treatments show promising results. The exact mechanism of the pathogenesis of the disease is still unknown, with current suggestions indicating the overlapping roles of the immune system, central nervous system, and neuroendocrine system. However, the pathological mechanism revolves around inflammatory and oxidative stress markers. Polyphenols are the most abundant secondary metabolites of plant origin, with potent antioxidant and anti-inflammatory effects, and can exert protective activity against a whole range of disorders. The current review is aimed at highlighting the emerging role of polyphenols in CFS from both preclinical and clinical studies. Numerous agents of this class have shown promising results in different in vitro and in vivo models of chronic fatigue/CFS, predominantly by counteracting oxidative stress and the inflammatory cascade. The clinical data in this regard is still very limited and needs expanding through randomized, placebo-controlled studies to draw final conclusions on whether polyphenols may be a class of clinically effective nutraceuticals in patients with CFS.