The aim of this study was to evaluate the protective effects of p-chloro-diphenyl diselenide (p-ClPhSe)(2) on depressant-like action and cognitive impairment caused by aging in male rats. For this purpose, old rats were orally treated with (p-ClPhSe)(2) (10 or 25 mg/kg) for seven days. Then, rats were tested in experimental models of ambulation, memory and depression. In addition, Na(+) K(+) ATPase activity and reactive species (RS) levels were measured in rat cortex and hippocampus. Our findings demonstrated that treatment of old rats with (p-ClPhSe)(2) (10 and 25 mg/kg) reversed spatial memory deficit in the object location test and depressant-like action in the forced swimming test (FST) caused by aging. Reduction in exploratory behavior (rearings) in the open-field test caused by aging was not altered by (p-ClPhSe)(2) administration. Moreover, the increase of RS levels and inhibition of Na(+) K(+) ATPase activity in cortex and hippocampus resulting from aging were restored by the highest dose of (p-ClPhSe)(2). To assess the mechanisms involved in the antidepressant-like effect of (p-ClPhSe)(2), old rats received WAY100635 (0.1 mg/kg, subcutaneous, a selective 5-HT(1A)R antagonist), ritanserin (1 mg/kg, intraperitoneal, a 5-HT(2A/2C)R antagonist) or ondansetron (1 mg/kg, intraperitoneal, a 5-HT(3)R antagonist) 15 min before (p-ClPhSe)(2) (25 mg/kg) treatment. After 30 min, the FST was performed. Results showed that in addition to the antioxidant action, the modulation of 5-HT(1A) and 5-HT(3) receptors may be at least partly involved in the antidepressant-like action elicited by (p-ClPhSe)(2) in old rats. These findings highlight the beneficial potential of (p-ClPhSe)(2) in aged male rats.