HYBID is a new hyaluronan-degrading enzyme and exists in various cells of the human body. Recently, HYBID was found to over-express in the osteoarthritic chondrocytes and fibroblast-like synoviocytes. According to these researches, high level of HYBID is significantly correlated with cartilage degeneration in joints and hyaluronic acid degradation in synovial fluid. In addition, HYBID can affect inflammatory cytokine secretion, cartilage and synovium fibrosis, synovial hyperplasia via multiple signaling pathways, thereby exacerbating osteoarthritis. Based on the existing research of HYBID in osteoarthritis, HYBID can break the metabolic balance of HA in joints through the degradation ability independent of HYALs/CD44 system and furthermore affect cartilage structure and mechanotransduction of chondrocytes. In particular, in addition to HYBID itself being able to trigger some signaling pathways, we believe that low-molecular-weight hyaluronan produced by excess degradation can also stimulate some disease-promoting signaling pathways by replacing high-molecular-weight hyaluronan in joints. The specific role of HYBID in osteoarthritis is gradually revealed, and the discovery of HYBID raises the new way to treat osteoarthritis. In this review, the expression and basic functions of HYBID in joints were summarized, and reveal potential role of HYBID as a key target in treatment for osteoarthritis.