Osteoarthritis (OA) is a common degenerative disease that results in joint inflammation as well as pain and stiffness. A previous study has reported that Cornus officinalis (CO) extract inhibits oxidant activities and oxidative stress in RAW 264.7 cells. In the present study, we isolated bioactive compound(s) by fractionating the CO extract to elucidate its antiosteoarthritic effects. A single bioactive component, morroniside, was identified as a potential candidate. The CO extract and morroniside exhibited antiosteoarthritic effects by downregulating factors associated with cartilage degradation, including cyclooxygenase‐2 (Cox‐2), matrix metalloproteinase 3 (Mmp‐3), and matrix metalloproteinase 13 (Mmp‐13), in interleukin‐1 beta (IL‐1β)‐induced chondrocytes. Further-more, morroniside prevented prostaglandin E2 (PGE2) and collagenase secretion in IL‐1β‐induced chondrocytes. In the destabilization of the medial meniscus (DMM)‐induced mouse osteoarthritic model, morroniside administration attenuated cartilage destruction by decreasing expression of inflammatory mediators, such as Cox‐2, Mmp3, and Mmp13, in the articular cartilage. Transverse microcomputed tomography analysis revealed that morroniside reduced DMM‐induced sclerosis in the subchondral bone plate. These findings suggest that morroniside may be a potential protective bioactive compound against OA pathogenesis.