Objective To study the effect and clinical significance of DKK1 on osteoarthritis (OA). Methods  In this study, 80 OA cases were selected as OA group, 80 patients without history of OA as normal control group. The serum level of DKK1 was measured by sandwich enzyme linked immunosorbent assay (ELISA) in both groups. The rabbit model of knee osteoarthritis was built. The pathological characteristics of control, model and DKK1 groups were contrasted and the Manikin score was assessed as well. The therapeutic effect of DKK1 was evaluated. Results The serum level of DKK1 in the OA group was significantly lower than that in the control group (P = 0.001). The rabbit model of knee osteoarthritis was built successfully. The Manikin score in the DKK1 group (7.89 ± 0.82) was significantly lower than that in the model group [(12.56 ± 0.51), P = 0.003], but was significantly higher than that in the control group [(1.08 ± 0.35), P = 0.001]. Conclusions As the Wnt signaling pathway inhibitor, DKK1 can inhibit osteoblast differentiation, restrain the course of OA; but its mechanism in the human body still needs further research.