Mitogen-activated protein kinase (MAPK) pathways are implicated in joint destruction in rheumatoid arthritis (RA) by modulating the production and functions of inflammatory cytokines. Although p38 MAPK (p38) participates in signaling cascades leading to osteolysis in arthritis, the mechanisms of its action in this process remain incompletely understood. Here, we found that the osteoclast (Ocl) precursors expressed p38α, but not p38β, p38δ, and p38γ isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-κB ligand (RANKL) resulted in p38 activation. Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-α was blocked with the novel p38 inhibitor 4-(3-(4-chlorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (SC-409). To validate in vitro data, p38 role was further investigated in streptococcal cell wall (SCW)-induced arthritis in rats. We found that SCW-induced joint swelling and bone destruction were attenuated by SC-409. Mechanistically, the data show that SCW-stimulated DNA binding activity of the transcription factor myocyte-enhancing factor 2 C, which is downstream of p38, was inhibited by SC-409. In addition, SC-409 inhibited SCW-stimulated expression of numerous factors, including TNF-α, interleukin-1β, and RANKL. Although c-Jun NH₂-terminal kinase and NF-κB pathways were activated in vitro by RANKL and in vivo by SCW, SC-409 had no significant effect on these pathways. In conclusion, our data show that p38 modulates the production and signaling of cytokines, thus providing a mechanism of the bone-sparing effect of SC-409 in rat arthritis. These data present SC-409 as a novel potent p38 inhibitor and suggest that p38-based therapies may be beneficial in preventing bone loss associated with RA.