BACKGROUND: The incidence of gouty arthritis (GA) has gradually increased, and modern drug therapies have obvious side effects. Guizhi Shaoyao Zhimu Decoction (GSZD), a classic prescription in Traditional Chinese Medicine for treating various osteoarthritis, has shown significant advantages in curing GA. PURPOSE: To verify the therapeutic effect of GSZD on GA and investigate its potential pharmacological mechanism via integrated analysis of the gut microbiota and serum metabolites for the first time. METHODS: The chemical composition of GSZD was determined using UPLC-MS. The GA rat model was established by the induction of a high-purine diet combined with local injection. We examined the effects and mechanisms of GSZD after 21 d using enzyme-linked immunosorbent assays, 16S rRNA, and non-targeted metabolomics. Finally, correlation analysis and validation experiment were performed to explore the association among the gut microbiota, serum metabolites, and GA-related clinical indices. RESULTS: In total, 19 compounds were identified as GSZD. High-purine feedstuff with local injection-induced arthroceles were significantly attenuated after GSZD treatment. GSZD improved bone erosion and reduced the serum levels of inflammatory factors (lipopolysaccharide, tumor cell necrosis factor-α, and interleukin) and key indicators of GA (uric acid). 16S rRNA analysis indicated that GSZD-treated GA rats exhibited differences in the composition of the gut microbiota. The abundance of flora involved in uric acid transport, including Lactobacillus, Ruminococcaceae, and Turicibacter, was elevated to various degrees, whereas the abundance of bacteria involved in inflammatory responses, such as Blautia, was markedly reduced after treatment. Moreover, serum metabolite profiles revealed 27 different metabolites associated with the amelioration of GA, which primarily included fatty acids, glycerophospholipids, purine metabolism, amino acids, and bile acids, as well as primary metabolic pathways, such as glycerophospholipid metabolism and alanine. Finally, correlation analysis of the heat maps and validation experiment demonstrated a close relationship among inflammatory cytokines, gut microbial phylotypes, and metabolic parameters. CONCLUSION: This study demonstrated that GSZD could modulate the gut microbiota and serum metabolic homeostasis to treat GA. In addition, the application of gut microbiota and serum metabolomics correlation analyses sheds light on the mechanism of Traditional Chinese Medicine compounds in the treatment of bone diseases.