Osteoarthritis (OA) is the most common form of arthritis and is a leading cause of disability with a large socioeconomic cost. OA is a whole-joint disease characterized by cartilage destruction, synovial inflammation, osteophyte formation, and subchondral bone sclerosis. To date, however, no effective disease-modifying therapies for OA have been developed. The estrogen-related receptors (ERRs), a family of orphan nuclear receptor transcription factors, are composed of ERRα, ERRβ, and ERRγ, which play diverse biological functions such as cellular energy metabolism. However, the role of ERRs in OA pathogenesis has not been studied yet. Among the ERR family members, ERRγ is markedly upregulated in human and various models of mouse OA cartilage. Adenovirus-mediated overexpression of ERRγ in the mouse knee joint tissue caused OA pathogenesis. Additionally, cartilage-specific ERRγ transgenic (Tg) mice exhibited enhanced experimental OA. Consistently, ERRγ in articular chondrocytes directly caused expression of matrix metalloproteinase (MMP) 3 and MMP13, which play a crucial role in cartilage destruction. In contrast, genetic ablation of Esrrg or shRNA-mediated Esrrg silencing in the joint tissues abrogated experimental OA in mice. These results collectively indicated that ERRγ is a novel catabolic regulator of OA pathogenesis and can be used as a therapeutic target for OA.