AIM: This study will clarify whether Wnt5a can be used as a potential diagnostic and therapeutic target for rheumatoid arthritis (RA) and how Xinfeng capsule (XFC) can improve RA through the Wnt5a/β-catenin signaling pathway. METHODS: ELISA and RT-qPCR were used to detect inflammatory factors and pathological genes in the rat model of AA in vivo to investigate the effect of XFC on AA rats. RT-qPCR was used to verify the core genes and key pathways of XFC regulation predicted by network pharmacology. The regulatory mechanism of XFC on Wnt/β-catenin pathway was elucidated by RT-qPCR. Western blot and immunofluorescence in primary AA fibroblast-like synovial cells (FLS) in vitro. RESULTS: XFC significantly decreased the arthritis score and paw swelling in AA rats, and inhibited joint inflammation in AA rats. XFC decreased the levels of inflammatory factors TNF-α and IL-1 in peripheral blood of AA rats, and inhibited the levels of pathological genes MMP3 and fibronectin in joint synovium and AA FLS of AA rats. Network pharmacology predicts that the Wnt pathway is highly correlated with XFC treatment of RA. At the cellular level, serum containing XFC inhibited the expression of Wnt pathway-related genes β-catenin, CCND1 and c-Myc. The molecular docking results showed that the key components of XFC had strong binding ability to Wnt5a, and the overexpression of Wnt5a (Wnt5a-ove) in AA FLS interfered with the action of XFC. CONCLUSION: The expression of Wnt5a is significantly increased in AA FLS and RA FLS, and XFC can inhibit the activation of Wnt/β-catenin signaling pathway to improve RA by binding with Wn5a, providing a new therapeutic mechanism for XFC to improve RA.