OBJECTIVE: To explore the potential therapeutic effects and underlying mechanism of vanillic acid (VA) in the treatment of rheumatoid arthritis (RA). METHODS: A collagen-induced arthritis (CIA) model was established in DBA/1 J mice. Methotrexate (MTX, 1 mg/kg/d) and VA (5 mg/kg/d, 10 mg/kg/d, 20 mg/kg/d) were then administered to investigate their therapeutic efficacy on RA in vivo. The body weight, joint score, and spleen index of the mice in different experimental groups were evaluated. Micro-CT was performed to detect joint destruction in the mice, and HE staining was utilized to observe the pathological conditions of their joints and spleens. Quantitative real-time PCR (qRT-PCR) and enzyme linked immunosorbent assay (ELISA) were used to detect inflammatory cytokines and chemokines. Changes in synovial tissue signaling pathways were detected using immunohistochemistry. For in vitro analysis, RAW 264.7 cells were pretreated with different concentrations of VA (25, 50, 100 μg/ml) and then treated with lipopolysaccharide (LPS), and changes in their signaling pathways were detected by western blot (WB). RESULTS: VA improved the clinical symptoms and bone destruction of arthritis in CIA mice, reduced pathological damage to ankle synovial and spleen tissue, and inhibited polarization of macrophages to M1 in the synovial tissue as well. In addition, VA inhibited the expression of TNF-α, IL-6, IL-1β, MCP-1, and iNOS in CIA mice and in LPS-stimulated RAW264.7 cells and also inhibited the phosphorylation of p65, IκBα, ERK, JNK, and p38 MAPKs. CONCLUSIONS: VA can significantly improve the clinical symptoms of RA and exerts anti-inflammatory effects by inhibiting the activation of the NF-κB/MAPK pathway.