<jats:p><jats:bold>BACKGROUND AND PURPOSE</jats:bold> Kalopanaxsaponin A, a triterpenoid saponin isolated from <jats:italic>Kalopanax pictus</jats:italic> (family <jats:italic>Araliaceae</jats:italic>), potently inhibited nuclear factor‐kappa B (NF‐κB) activation in lipopolysaccharide (LPS)‐stimulated peritoneal macrophages during a screening programme for anti‐colitis agents from natural products. Its anti‐inflammatory mechanism remains unknown. Therefore, we investigated its anti‐inflammatory effects in lipopolysaccharide (LPS)‐ or peptidoglycan‐stimulated murine peritoneal macrophages and trinitrobenzene sulphonic acid (TNBS)‐induced colitic mice.<jats:p><jats:bold>EXPERIMENTAL APPROACH</jats:bold> Peritoneal macrophages from male ICR mice were stimulated with LPS or peptidoglycan <jats:italic>in vitro</jats:italic> and treated with kalopanaxsaponin A. Colitis was induced <jats:italic>in vivo</jats:italic> by intrarectal administration of TNBS in male ICR mice. Mice were treated daily with kalopanaxsaponin A, sulphasalazine or phosphate‐buffered saline. Inflammatory markers, cytokines, enzymes and transcription factors were measured by ELISA, immunoblot, flow cytometry and immunofluorescent confocal microscopy.<jats:p><jats:bold>KEY RESULTS</jats:bold> Kalopanaxsaponin A potently inhibited the expression of the pro‐inflammatory cytokines, interleukin (IL)‐1β, tumour necrosis factor (TNF)‐α and IL‐6, induced by LPS, but not that induced by TNF‐α, in peritoneal macrophages. However, it potently increased the expression of the anti‐inflammatory cytokine IL‐10. Kalopanaxsaponin A inhibited activation of the IL‐1 receptor‐associated kinase (IRAK)‐1, inhibitor of κB kinase‐β, NF‐κB and mitogen‐activated protein kinases (extracellular signal‐regulated kinase, c‐Jun NH<jats:sub>2</jats:sub>‐terminal kinase, p‐38), but LPS/Toll‐like receptor‐4 interaction and IRAK‐4 activation were not affected. Oral administration of kalopanaxsaponin A (10 and 20 mg·kg<jats:sup>−1</jats:sup>) improved the clinical parameters and histology <jats:italic>in vivo</jats:italic>. Kalopanaxsaponin A inhibited NF‐κB and mitogen‐activated protein kinase activation induced by TNBS by suppressing IRAK‐1 activation.<jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS</jats:bold> Kalopanaxsaponin A may improve inflammatory diseases, such as colitis, by inhibiting IRAK‐1 activation.