Aim To study the protective effect of curcumin on vascular calcification in rat model. Methods30 male SD rats were randomly divided into 3 groups, 10 in each group, namely the control group, the calcification group and the intervention group. Vitamin D3 and nicotine were used to establish vascular calcification model. Vascular calcification was detected by von Kossa staining, calcium content and the activity of alkaline phosphatase (ALP) were detected by kit, Western blot was used to detect the protein expression of bone morphogenetic protein-2 (BMP-2), Runx2 and cathepsin D (CTSD), immunohistochemical staining was used to observe the expression and distribution of CTSD in blood vessels. Results Vitamin D3 and nicotine could induce vascular calcification, increase calcium content and the activity of ALP, and upregulate the expression of BMP-2 and Runx2. Meanwhile, curcumin could play a protective effect against the vascular calcification, decrease calcium content and the activity of ALP, and downregulate the expression of BMP-2 and Runx2 induced by Vitamin D3 and nicotine. Furthermore, CTSD was upregulated and distributed in extracellular matrix after treated with Vitamin D3 and nicotine. Curcumin could downregulate the expression of CTSD and reduce its distribution in extracellular matrix. Conclusion Curcumin could inhibit vascular calcification in rat model induced by vitamin D3 and nicotine and it may play protective role via regulating the expression of CTSD.