The joint disease osteoarthritis (OA) is the most common form of arthritis, which mainly affects the older people. OA is becoming one of the major non-fatal health burdens of the world. The etiology of OA is mostly unclear, and it cannot be cured totally. Osteopontin (OPN) is a multifunctional phosphoprotein, of which overexpression and high level of presence in synovial fluid and articular cartilage were found to be associated with OA progression. Usually, in OA progression, OPN plays important role as an intrinsic regulator. Recent studies have taken attempt to use this protein as a diagnostic marker of OA and use OPN as a target for the drug development against OA. This review summarizes the role of OPN in OA, with focusing on the mechanism of action, and also discussing the diagnostic and therapeutic aspects of OA related to OPN.