It is believed that physical stress, infection and oxidative stress are involved in the development of chronic fatigue syndrome. There is little evidence stating the beneficial role of nutritional supplements in chronic fatigue syndrome. Based on this, this study was designed to evaluate the effect of naringin, a natural polyphenol, in a mouse model of immunologically-induced fatigue, wherein purified lipopolysaccharide (LPS) as well as Brucella abortus (BA) antigen was used as immunogens. The assessment of chronic fatigue syndrome was based on chronic water-immersion stress test for 10 mins as well as measurement of hyperalgesia for 19 days. Immobility time and tail withdrawal latency as well as oxidative stress were taken as the markers of fatigue. Mice challenged with LPS or BA for 19 days showed significant increase in the immobility time, hyperalgesia and oxidative stress on 19th day. Serum tumor necrosis factor-alpha (TNF-α) levels markedly increased with LPS or BA challenge. Concurrent treatment with naringin resulted in the significant decrease in the immobility time as well as hyperalgesia. There was significant attenuation of oxidative stress as well as in TNF-α levels. Present findings strongly suggest the role of oxidative stress and immunological activation in the pathophysiology of chronic fatigue syndrome, and treatment with naringin can be a valuable option in chronic fatigue syndrome.