This study systematically evaluated the therapeutic effects of the traditional Yao medicine Sifangteng formula (SFTF) on rheumatoid arthritis (RA) using a collagen-induced arthritis (CIA) rat model. Multi-omics approaches, including widely targeted metabolomics, TMT-based quantitative proteomics, network pharmacology, WGCNA, and single-cell RNA sequencing analysis, were integrated to identify active components and key molecular targets. The results demonstrated that SFTF attenuates synovial inflammation and joint destruction by regulating the STAT3-MMPs axis. Key bioactive compounds such as quercitrin, hesperidin, and luteolin-7,3'-di-O-glucoside were identified and validated in vitro. This study provides a mechanistic basis for the traditional use of Sifangteng in RA treatment.