Purpose: This study was conducted to assess the antidepressant effects of capsaicin in chronic depressive rats and elucidate the mechanism underlying its effects. Methods: Male Wistar rats (280~320 g, 8 weeks of age) were subjected to depression induced by chronic unpredictable mild stresses. The rats were exposed to 8 kinds of stresses for 8 weeks. In the last 2 weeks, fluoxetine or capsaicin was injected subcutaneously. The dose of fluoxetine was 10 mg/kg (body weight), while the doses of capsaicin consisted of low (1 mg/kg), middle (5 mg/kg), and high(10 mg/kg). The forced swim test (FST) was conducted to evaluate the immobility time of rats. The immobility time indicates despair, one of symptoms of depression. The change of tryptophan hydroxylase (TPH) in the dorsal raphe was investigated using immunohistochemistry. In the hippocampus cornu ammonis (CA) 1 and 3, glucocorticoid receptor (GR) expression was measured. Results: The immobility time in the FST was significantly lower (p < .05) in the low-dose (M = 32.40 ± 13.41 seconds) and middle-dose (M = 28.48 ± 19.57 seconds) groups than in the non-treated depressive rats (M = 90.19 ± 45.34 seconds). The amount of TPH in the dorsal raphe was significantly higher (p < .05) in the middle-dose (M = 249.17 ± 35.02) and high-dose (M = 251.0 ± 56.85) groups than in the non-treated depressive rats (M = 159.78 ± 41.16). However, GR expression in the hippocampus CA1 and CA3 did not show significant differences between the non-treated depressive rats and the capsaicin-injected rats. Conclusion: This study suggests that capsaicin produces an antidepressant-like effect on chronic unpredictable mild stress-induced depression in rats via the serotonin biosynthesis pathway.