Objective To explore the effects of Zhizichi Decoction on inflammation levels and neurotransmitters in the brain of anxiety disorder rat model based on the CXCL12/CXCR4 biological axis. Methods Ninety rats were randomly divided into Control group, chronic restraint stress group (CRS group), Diazepam group, low-dose Zhizichi Decoction group (ZZCD-L group), high-dose Zhizichi Decoction group (ZZCD-H group) and CXCL12/CXCR4 pathway inhibitor (AMD3100 group), with fifteen rats in each group. Chronic restraint stress was used to create rats model of anxiety disorder. Diazepam group, AMD3100 group, ZZCD-L group, and ZZCD-H group rats were treated with Diazepam (1 mg/kg), AMD3100 (1 mg/kg) and Zhizichi Decoction (400 mg/kg, 800 mg/kg), respectively. After 14 days of confinement, the elevated cross maze experiment and open field experiment were used to evaluate anxiety like behavior in rats. ELISA was used to detect inflammatory factors (IL-1β, IL-6 and TNF-α) content in rat serum, neurotransmitters (5-HT, Glu, GABA) content and Glu/GABA ratio in hippocampal tissues. RT-qPCR was used to detect CXCL12 and CXCR4 mRNA levels in hippocampal tissues. Western blot was used to detect 5-HT receptors (5-HT1AR, 5-HT2AR), GABA receptors (GABAAR、GABABR), Glu receptors (GluA1, GluA2) and CXCL12, CXCR4 protein levels in hippocampal tissues.Results Compared with Control group, the anxiety like behavior in CRS group rats were significantly increased, IL-1β, IL-6, TNF-α levels in serum, 5-HT, GABA, 5-HT1AR, 5-HT2AR, GABAAR, GABABR levels in hippocampal tissues were significantly decreased, Glu, Glu/GABA, GluA1 GluA2 levels, CXCL12, CXCR4 mRNA and protein levels were significantly increased (P＜0.05); Zhizichi Decoction could alleviate anxiety like behavior in rats and inhibit serum inflammatory factor IL-1β, IL-6, TNF-α levels, brain neurotransmitter Glu levels, CXCL12, CXCR4 mRNA and protein levels, and increase neurotransmitter 5-HT and GABA levels, And it shows a dose-dependent effect of Zhizichi Decoction (P＜0.05). And the effect of Zhizichi Decoction was similar to AMD3100 (P＞0.05).Conclusion Zhizichi Decoction could alleviate anxiety like behavior in rats, inhibit inflammation levels and Glu level in Hippocampal tissue, and increase 5-HT and GABA levels. It might exert regulatory effects by inhibiting the CXCL12/CXCR4 biological axis