To investigate the therapeutic effects of Cynanchum paniculatum root extract on rheumatoid arthritis (RA) and to reveal the underlying molecular mechanisms. A rat ( Rattus norvegicus ) model of antigen-induced rheumatoid arthritis (AIA) was constructed using complete freund’s adjuvant (CFA), and normal and AIA rats without drug administration were then used as control and model groups, and AIA rats with oral doses of 100, 250, and 500 mg·kg -1 of C. paniculatum root extract and 0.51 mg·kg -1 methotrexate were used as the low, medium, and high dose groups and positive drug group, respectively. Subsequently, paw swelling, body weight, and organ index of rats were measured, and enzyme-linked immunosorbent assay was used to detect serum pro-inflammatory factor levels, myeloperoxidase (MPO) content in ankle tissues, and RT-qPCR to detect the mRNA expression levels of key genes of the NF -κ B pathway. In addition, gas chromatography-mass spectrometry (GC-MS) was used to analyze and identify the components of the C. paniculatu root extract. The results showed that: 1) Compared with the model group, the degree of claw swelling was significantly reduced in the low, medium and high dose groups. And serum levels of tumor necrosis factor -α (TNF- α ) and interleukin 6 (IL-6) as well as MPO content in ankle tissues were significantly reduced ( p <0.001) in a dose-dependent manner. In addition, the body weight and the growth and development of immune organs of these three groups of rats were not affected by the extract of C. paniculatum root. 2) RT-qPCR results showed that the mRNA expression levels of NF-κB, TNF-α, IL-6, and interleukin 1 β genes were significantly ( p <0.001) decreased by the positive drug group and medium and high dose groups of C. paniculatum root extract compared with the model group in a dose-dependent manner. 3) GC-MS results showed that the root extract of C. paniculatu mainly contained paeonol, palmitic acid, linoleic acid, and 5-hydroxymethylfurfural. It is clear from the above results that C. paniculatum root extract showed good RA therapeutic effects, which may act primarily through paeonol and linoleic acid, and the preliminary reveals that its therapeutic mechanism may be related to the regulation of NF -κ B pathway.