Vascular calcification is a cell-mediated active biological process, similar to bone remodeling, and plays an important role in the occurrence and evolution of acute and chronic cardiovascular and cerebrovascular events. In recent years, the research on the mechanism and prevention of vascular calcification has gradually attracted the attention of scholars, but unfortunately, precise molecular and cellular targeted therapy for clinical application is rare. Previous studies have shown the presence of the osteoblast phenotype and dysfunctional osteoclasts in atherosclerotic plaques of diabetes. The imbalance of osteoblasts and osteoclasts may be the key step in calcification development in atherosclerotic plaques. It is known that macrophage-derived osteoclasts are the only cells with bone resorption activity and have the potential to reverse calcification. Therefore, exploring the bone resorption activity of macrophage-derived osteoclasts in the plaque is a promising direction to bring new breakthroughs in the prevention and treatment of calcification. However, the role and related regulatory mechanism of osteoclasts in vascular calcification may still be controversial nowadays. Based on the research progress that has been made in this field and the experimental results of our research group, this article puts forward the hypothesis that Nε-carboxymethyl-lysine (CML) mediates NFATc1-GNPTAB through STAT3 to regulate the osteoclastic absorption barrier of macrophages in plaques and provides a brief review of the following 4 aspects: concept and mechanism of vascular calcification, relationship between osteoclasts and vascular calcification, mechanism of osteoclasts in vascular calcification, and osteoclasts as a therapeutic target for vascular calcification. It is hoped that this paper will offer a new entry point for the precise prevention and treatment of vascular calcification.