Background and Purpose The pathogenesis of osteoarthritis implicates a low‐grade inflammation associated to the innate immune system activation. Toll like receptor (TLR) stimulation triggers the release of inflammatory mediators, which aggravate osteoarthritis. We studied the preventive effect of 6‐shogaol, a potential TLR4 inhibitor, on the treatment of experimental knee osteoarthritis. Experimental Approach Osteoarthritis was induced in C57BL6 mice by surgical section of the medial meniscotibial ligament, which received 6‐shogaol for eight weeks. Cartilage damage, inflammatory mediator presence and disease markers were assessed in joint tissues by immunohistochemistry. Computational modelling was used to predict binding modes of 6‐shogaol into the TLR4/MD2 receptor and its permeability across cellular membranes. Employing LPS‐stimulated chondrocytes and MAPK assay, we elucidated 6‐shogaol action mechanisms. Key Results 6‐Shogaol treatment prevented articular cartilage lesions, synovitis and the presence of pro‐inflammatory mediators, and disease markers in osteoarthritis animals. Molecular modelling studies predicted 6‐shogaol interaction with the TLR4/MD‐2 heterodimer in an antagonist conformation through its binding into the MD‐2 pocket. In cell culture, we confirmed that 6‐shogaol reduced LPS‐induced TLR4 inflammatory signalling pathways. Besides, MAPK assay demonstrated that 6‐shogaol directly inhibits the ERK1/2 phosphorylation activity. Conclusion and Implications 6‐Shogaol evoked a preventive action on cartilage and synovial inflammation in osteoarthritis mice. 6‐shogaol effect may take place not only by hindering the interaction between TLR4 ligands and the TLR4/MD‐2 complex in chondrocytes, but also through inhibition of ERK phosphorylation, implying a pleiotropic effect on different mediators activated during osteoarthritis, which proposes it as an attractive drug for osteoarthritis treatments.