Huang-Lian-Jie-Du-Tang (HLJDT) is a traditional Chinese medicine (TCM) with anti-inflammatory activity. The present study used a metabolomic approach based on LC-Q-TOF-MS to profile rheumatoid-arthritis- (RA-) related metabolic changes and to investigate the interventional mechanisms of HLJDT in collagen-induced arthritis rats. Forty male Wistar rats were randomly divided into five groups: (1) a model group, (2) a normal control group, (3) a dexamethasone group, (4) a HLJDT group, and (5) a group that received 13 components of HLJDT. Plasma samples were collected 8, 15, and 22 days after the rats were injected with bovine type II collagen. By combining variable importance in the projection values with partial least squares discriminant analysis, 18 potential biomarkers were identified in the plasma samples. The biomarkers were primarily involved in glycerophospholipid metabolism, fatty acid metabolism, tryptophan metabolism, linoleic acid metabolism, phenylalanine metabolism, purine metabolism, arachidonic acid metabolism, and bile acid biosynthesis. Using the potential biomarkers as a screening index, the results suggest that HLJDT can potentially reverse the process of RA by partially regulating fatty acid oxidation and arachidonic acid metabolism. This study demonstrates that a metabolomic strategy is useful for identifying potential RA biomarkers and investigating the underlying mechanisms of a TCM in RA treatment.