An experimental model of chronic fatigue syndrome (CFS) is utilized for evaluation of antidepressant, anti-stress effects, wherein the rat is forced to swim in water for 15 min/day on 21 consecutive days. Rats were divided into stressed control, stressed plus standard drug (Panax ginseng) and stressed plus 200 and 500 mg/kg of test drug, i.e., Nardostachys jatamansi extract (NJE) given orally. The immobility during each 5 min periods of 0–5, 5–10 and 10–15 min of stress were noted. Similarly the climbing (struggling) behaviour was noted in the above four groups of rats in intervals of 5 min. The locomotor activity and also the anxiety state in animals were evaluated in an elevated plus maze after CFS in all the four groups. There was a significant increase in despair behaviour and anxiety in stressed control animals on successive days of CFS. Locomotor activity gradually decreased in stressed control group. Treatment with NJE (200 and 500 mg/kg) significantly reversed both paradigms. Biochemical analysis showed that CFS significantly increased lipid peroxidation, nitrite and superoxide dismutase levels and decreased catalase level in rat brain. Administration of NJE (200 and 500 mg/kg) tended to normalize both augmented lipid peroxidation, nitrite, superoxide dismutase activities and catalase level significantly. NJE per se has an antioxidant effect. The results indicate that CFS may lead to oxidative stress, which is mitigated by NJE and so its antioxidant property may be responsible for anti-stress effect of NJE.