Degradation of extracellular matrix such as type II collagen and aggrecan induced by proinflammatory cytokines has been considered as an important hallmark of Osteoarthritis (OA). Roxatidine is a licensed specific competitive H (2) −receptor antagonist used for the treatment of gastric and duodenal ulcers. The pharmacological function of roxatidine on Osteoarthritis (OA) remains unknown. In the current study, we report that roxatidine attenuated TNF-α- induced degradation of type II collagen by suppressing the expression of MMP-3 and MMP-13 in human chondrosarcoma cell line SW1353 cells. In addition, roxatidine ameliorated TNF-α- induced reduction of aggrecan by inhibiting the expression of ADAMTS-4 and ADAMTS-5. Notably, results indicate that roxatidine ameliorated TNF-α- induced the phosphorylations of IKK, IκBα, and NF-κB p65 as well as nuclear translocation of NF-κB p65 and the transcriptional activity of NF-κB, suggesting that roxatidine abolished the activation of NF-κB signaling pathway. Our findings implicate that roxatidine might be considered as an anti-osteoarthritic agent.