To study the antidepressant effects of Peiyuan Jieyu Decoction and its regulation on the tryptophan-kynurenine ( TRP-KYN)pathway. Methods:The mice model was established by acute stress. The immobility time in forced swimming test was acquired and analysed by Noldus EthoVision XT9 system. The content of tryptophan and kynurenine in brain tissue were detected by HPLC-MS/MS technique. The mRNA expression level of tryptophan 2,3-dioxygenaes (TDO) in liver tissue was detected by real-time PCR. Results:Acute stess induced prolong of immobility time of Balb/c mice (P<0.05). The TDO activity in liver tissue and the TDO mRNA expression level increased (P<0.01). Tiansi Decoction and Peiyuan Jieyu Decoction could shorten the immobility time of mice (P<0.05) and reduce the TDO mRNA expression. The inhibitory effect of Quinolinic acid by Tiansi Decoction was more significant. Conclusion:Tiansi Decoction and Peiyuan Jieyu Decoction has antidepressant effect. This effect may be related to the decrease of serum corticosterone levels after acute stress and the reduction of the TDO mRNA expression. Tiansi Decoction shows obvious inhibition to neurotoxins which may be related to the regulation of KYN metabolites.