Several studies have proven the ability of NEL-like molecule-1 (Nell-1) to induce chondrogenesis and make it as a potential candidate for articular cartilage repair. In the current study, the chondroprotective effect of Nell-1 on osteoarthritis (OA) of the temporomandibular joint (TMJ) was investigated by intra-articular injection. Bilateral partial discectomy was performed in 24 rabbits to induce TMJOA. Four weeks later, the right TMJ was treated with Nell-1 as the experimental group, whereas the left was treated with physiologic saline as the control group. Twelve rabbits each time were randomly killed at 12 and 24 weeks after injection, respectively. Histologic observation and metabolic analysis by reverse transcription-polymerase chain reaction were used for evaluation. All TMJs appeared as OA-like histologic changes after intra-articular injection. However, the degree of osteoarthritis in the experimental group was less severe than that in the control group during the experimental time. The expression of type II collagen and aggrecan messenger RNA was significantly higher than the control group at 12 weeks after injection. However, no difference in the expression of aggrecanase or interleukin 1 messenger RNA was observed. The results suggest that intra-articular injection of Nell-1 may be a good alternative for the treatment of cartilage degeneration in OA.