Nigella sativa L. (Black seed), is a traditional herbal medicine that has been used for many purposes. The present study was designed to investigate the effects of hydro-alcoholic extract of nigella sativa L. (NS) on performance of Forced Swimming Test (FST), blood biochemical parameters related to fatigue and thyroid functions. Therefore, Blood Urea Nitrogen (BUN), Creatine Kinase (CK), Lactic Dehydrogenase (LDH), and Total Protein (TP), triiodothyronine T3, thyroxin T4 and TSH tests were investigated. Thirty five male adult mice were randomly divided into five groups: three NS-fed groups, one fluoxetine treated group and one control group. Three NS experimental groups received hydro-alcoholic extract of NS at doses of 50, 100 and 200 mg/kg orally for two weeks. Immobility time decreased in all NS groups compared with control group. Administration of NS significantly increased the concentration of T3 and T4 of the treatment groups. On the contrary, the amount of BUN, CK, LDH, TP and TSH decreased. In conclusion, black seed extract at the experimented doses showed anti-depressant, anti-fatigue and hyperthyroid effects.