ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is known as "Fawang" in Zhuang medical theory. Longzuantongbi granules (LZTBG) is an in-hospital preparation used at the First Affiliated Hospital of the Guangxi University of Chinese Medicine. This medicine is based on traditional Zhuang medicine theory for the treatment of "Fawang", and has an effectiveness of over 86.67%. It comprises eight medicinal materials, including the main drug Toddalia asiatica (L.) Lam. and Kadsura coccinea (Lem.) A.C. Smith, the assisting drugs Alangium chinense (Lour.) Harms, Zanthoxylum nitidum (Roxb.) DC., Sinomenium acutum (Thunb.) Rehd.et Wils., Bauhinia championii (Benth.) Benth., Spatholobus suberectus Dunn, and Ficus hirta Vahl. All of these herbs are commonly used in Zhuang medicine. AIM OF THE STUDY: This study aims to reveal the effect of LZTBG on collagen-induced arthritis (CIA) rats, to discover the potential efficacy-related biomarkers and explore the intervention mechanism of LZTBG from a molecular level, based on metabolomics. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were randomly assigned into a normal group, a CIA model group, a positive control (MTX) group and two different LZTBG treatment groups (5.4 g/kg/d and 2.7 g/kg/d). Body weight, arthritis index (AI), paw swelling, and hematoxylin and eosin (HE) staining experiments were used to evaluate the efficacy of the established model. A metabolomics method based on an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was established to analyze plasma taken from the rats, and to explore the interventional mechanism of LZTBG. RESULTS: LZTBG showed a positive effect on the CIA model rats. Thirty-one differential metabolites were screened out, and combined with pathway analysis, 11 potential efficacy-related biomarkers were then mapped in the pathway. These included linoleic acid (LA), phosphatidylcholine (PC), lysophosphatidylcholine (LPC), arachidonic acid (AA), 12-HETE, alpha-linolenic acid (ALA), 13(S)-HOT, 2-oxobutanoate, 3-hydroxybutyric acid, L-Valine, and acetylcholine. Furthermore, it was found that these metabolites may exhibit an intervention effect by means of modulating pathways related to both lipid metabolism and amino acid metabolism to associated with inflammation. CONCLUSION: LZTBG can effectively alleviate symptoms of RA, an effect that can primarily be attributed to the regulation of multiple pathways and multiple targets These results demonstrate that LC-MS/MS-based metabolomics is an advantageous technique for the investigation of the intervention effect and molecular mechanism of traditional compound medicine.