Osteoarthritis (OA), a disabling joint inflammatory disease, is characterized by the progressive destruction of cartilage, subchondral bone remodeling, and chronic synovitis. Due to the prolongation of the human lifespan, OA has become a serious public health problem that deserves wide attention. The development of OA is related to numerous factors. Among the factors, nitric oxide (NO) plays a key role in mediating this process. NO is a small gaseous molecule that is widely distributed in the human body, and its synthesis is dependent on NO synthase (NOS). NO plays an important role in various physiological processes such as the regulation of blood volume and nerve conduction. Notably, NO acts as a double-edged sword in inflammatory diseases. Recent studies have shown that NO and its redox derivatives might be closely related to both normal and pathophysiological joint conditions. They can play vital roles as normal bone cell-conditioning agents for osteoclasts, osteoblasts, and chondrocytes. Moreover, they can also induce cartilage catabolism and cell apoptosis. Based on different conditions, the NO/NOS system can act as an anti-inflammatory or pro-inflammatory agent for OA. This review summarizes the studies related to the effects of NO on all normal and OA joints as well as the possible new treatment strategies targeting the NO/NOS system.