Objective Tumor necrosis factor α–stimulated gene 6 (TSG‐6) is an anti‐inflammatory protein highly expressed in osteoarthritis (OA), but its influence on the course of OA is unknown. Methods Cartilage injury was assessed by murine hip avulsion or by recutting rested explants. Forty‐two previously validated injury genes were quantified by real‐time polymerase chain reaction in whole joints following destabilization of the medial meniscus (DMM) (6 hours and 7 days). Joint pathology was assessed at 8 and 12 weeks following DMM in 10‐week‐old male and female fibroblast growth factor 2 (FGF2)−/−, TSG‐6−/−, TSG‐6tg (overexpressing), FGF2−/−;TSG‐6tg (8 weeks only) mice, as well as strain‐matched, wild‐type controls. In vivo cartilage repair was assessed 8 weeks following focal cartilage injury in TSG‐6tg and control mice. FGF2 release following cartilage injury was measured by enzyme‐linked immunosorbent assay. Results TSG‐6 messenger RNA upregulation was strongly FGF2‐dependent upon injury in vitro and in vivo. Fifteeen inflammatory genes were significantly increased in TSG‐6−/− joints, including IL1α, Ccl2, and Adamts5 compared with wild type. Six genes were significantly suppressed in TSG‐6−/− joints including Timp1, Inhibin βA, and podoplanin (known FGF2 target genes). FGF2 release upon cartilage injury was not influenced by levels of TSG‐6. Cartilage degradation was significantly increased at 12 weeks post‐DMM in male TSG‐6−/− mice, with a nonsignificant 30% reduction in disease seen in TSG‐6tg mice. No differences were observed in cartilage repair between genotypes. TSG‐6 overexpression was unable to prevent accelerated OA in FGF2−/− mice. Conclusion TSG‐6 influences early gene regulation in the destabilized joint and exerts a modest late chondroprotective effect. Although strongly FGF2 dependent, TSG‐6 does not explain the strong chondroprotective effect of FGF2.