Osteoarthritis (OA) is one of the most common chronic degenerative diseases, which mainly damages articular cartilage and involves the entire joint tissue. In recent years, the incidence rate of the disease has gradually increased among middle-aged and elderly people. The specific etiology and pathogenesis are still unclear, and its occurrence is related to the patient’s age, hormone level, weight, inflammation, trauma, heredity and other factors. Chondroitin sulfate (CS) is a type of sulfated glycosaminoglycan that is widely presented in the extracellular matrix and cartilage of animal tissues. It plays a role in maintaining homeostasis in various intracellular environments, such as inflammation regulation, reactive oxygen species regulation, immune regulation, and tissue adhesion regulation. In recent years, the research on how CS inhibits OA has become more and more in-depth, and biomaterials derived from CS have also become the focus of research in recent years, such as chondroitin sulfate based hydrogels, biological scaffolds and drug delivery systems are being widely used. Therefore, this article systematically reviewed the latest progress of chondroitin sulfate and its derived biomaterials in the treatment of osteoarthritis, focusing on OA development inhibition induced by regulation of CS in the immune microenvironment of cartilage, synovium, and subchondral bone, cartilage matrix metabolism, as well as the application of its derived biomaterials in OA.