Objective To investigate the mechanism of the antidepressant-like effects of Chaihu Guizhi decoction (CGD). Methods Chaihu Guizhi decoction at the daily dose of 17 g/kg and solvent vehicle were administered by gavage in 12 and 14 male C57BL/6J mice for 7 consecutive days, respectively. Forced swimming test (FST), elevated plus maze (EPM) test, open field test (OFT) and novelty-suppressed feeding test (NSF) were performed to assess the depression- and anxiety-like behaviors and motor ability of the mice. We further used chronic social defeat stress (CSDS) and social interaction test to evaluate the antidepressant-like effects of CGD in comparison with the solvent vehicle. Western blotting and RT-qPCR were performed to detect the expressions of sirt1, p53, acetylated p53, and the neuron plasticity-related genes including synapsin I (Syn1), Rab4B, SNAP25 and tubulin beta4b in the hippocampus of the mice. Results In FST, the immobility time of CGD-treated mice was decreased significantly (P<0.05); no significant differences were found in the performances in EPM, NSF and OFT tests between the two groups. In social interaction test, the mouse models of CSDS treated with CGD showed significantly increased time in the interaction zone (P<0.05). Compared with those in the vehicle group, the CGD-treated mouse models exhibited significantly increased protein level of SIRT1 and decreased p53 acetylation (P<0.05) with up- regulated synapsin I mRNA expression in the hippocampus (P<0.05); no significant difference were found in Rab (P=0.813), SNAP (P=0.820), or Tubb mRNA expressions (P=0.864) between the two groups. Conclusion CGD produces antidepressant-like effects in mice possibly through the sirt1-p53 signaling pathway and synaptic plasticity.