Background: Rheumatoid arthritis (RA) is a systemic infi ammatory disease and mainly affects in the synovial joints. However, little information is available regarding the etiological mechanisms on the RA and natural compounds reducing RA symptom. Here, we investigated whether kaempferol, a natural compound abundantly found in editable plants, could target kinase domain of fi broblast growth factor (FGF) receptor (FGF-R), that is a well-known receptor tyrosine kinase implicated in RA pathogenesis. Methods: RA and osteoarthritis (OA) synovium tissues were used for immunohistofi uorescence assay and immunohistochemical staining. Mouse embryonic fi broblasts were used to investigate FGF-mediated cell migration study. Autoimmune arthritiswas induced by type II collagen (CII) immunization in DBA/1J mice. Kaempferol (2mg/ kg) was administered orally three times per week. The frequencies of IL-17-producing CD4+ T (Th17) cells and CD4+ CD25+ Foxp3+ regulatory T (Treg) cells were analyzed by fi ow cytometry. Results: Phosphorylation of the FGFR3 and RSK2 was highly detected in RA tissues compared with OA. KI-67, a cell proliferation marker, was higher in RA than that of OA. Cell migration induced by FGF was mediated through RSK2, and kaempferol inhibited FGF-induced cell migration by suppression of RSK2-mediated activities of the AP-1 and NF-κB and gene expression of COX-2. We found that active RSK2 positive cells were extensively co-stained with CD68 in RA synovium. Kaempferol inhibited FGF-induced synovial cell migration through RSK2-mediated signaling pathway. Kaempferol treatment suppressed arthritis severity in mice with autoimmune arthritis through suppression of Th17 and reciprocal induction of Treg cells in vivo. Infi ammation and joint destruction were signifi cantly suppressed in the joints of kaempferol- treated mice. Conclusions: Dual targeting of kaempferol on FGFR and RSK2 could be a novel therapeutic strategy in RA.