<jats:title>ABSTRACT</jats:title><jats:sec><jats:label /><jats:p>Proinflammatory cytokine interleukin‐1β (IL‐1β) stimulates several mediators of cartilage degradation and plays an important role in the pathogenesis of osteoarthritis (OA). Honokiol, a low molecular weight natural product isolated from the <jats:italic>Magnolia officinalis</jats:italic>, has been shown to possess anti‐inflammatory effect. Here, we used an in vitro model of cartilage inflammation to investigate the therapeutic potential of honokiol in OA. Human OA chondrocytes were cultured and pretreated with honokiol (2.5–10 µM) with or without IL‐1β (10 ng/ml). Nitric oxide (NO) production was quantified by Griess reagent. Prostaglandin (PG)E<jats:sub>2</jats:sub>, metalloproteinase‐13 (MMP‐13), and interleukin‐6 (IL‐6) productions were quantified by enzyme‐linked immunosorbent assay. The expressions of collagen II, cyclooxygenase‐2 (COX‐2), inducible nitric oxide synthase (iNOS), and nuclear factor κB (NF‐κB)‐related signaling molecules were determined by Western blotting. Our data showed that IL‐1β markedly stimulated the expressions of iNOS and COX‐2 and the productions of NO, PGE<jats:sub>2</jats:sub>, and IL‐6, which could be significantly reversed by honokiol. Honokiol could also suppress the IL‐1β‐triggered activation of IKK/IκBα/NF‐κB signaling pathway. Moreover, honokiol significantly inhibited the IL‐1β‐induced MMP‐13 production and collagen II reduction. Taken together, the present study suggests that honokiol may have a chondroprotective effect and may be a potential therapeutic choice in the treatment of OA patients. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:573–580, 2014.</jats:sec>