Sini Tang, a Chinese traditional prescription containing three herbs, has been widely used for Yang-deficiency. Recent clinical studies have shown that Sini Tang could treat and improve depression symptoms, but the mechanisms underlying the antidepressant effect of Sini Tang remains unknown. In rats with chronic unpredictable stress (CUS), we examined the effects of Sini Tang on sucrose preference and open field exploratory behavior. The levels of corticosterone level in plasma and corticotropin-releasing hormone (CRH) mRNA expression in hypothalamus were also measured by enzyme-linked immunosorbent assays (ELISA) and real-time reverse transcription PCR (RT-PCR), respectively. Rats subjected to CUS exhibited decreases in sucrose preference and ambulation in the open field test. These were all attenuated by Sini Tang in a dose-dependent manner. Biochemically, Sini Tang also reversed CUS-induced increases in corticosterone in plasma and CRH mRNA in the hypothalamus. The behavioral effects of the Sini Tang were correlated to the biochemical actions. These results suggest that Sini Tang produces an antidepressant-like effect, which appears to involve CRH in the brain.