In patients with diabetes, the Wnt/β-catenin pathway in vascular smooth muscle cells (VSMCs) is continuously activated by low-intensity inflammation, which leads to the osteoblastic differentiation of these cells and the deposition of calcium and phosphorus in blood vessels. The aim of the present study was to determine whether long intergenic non-coding RNA-erythroid pro-survival (lincRNA-EPS) was able to ameliorate vascular calcification (VC) associated with diabetes. VSMCs isolated from C57BL/6 mice were transfected with lincRNA-EPS overexpression vector in vitro and their osteoblastic differentiation was evaluated under high-glucose conditions. In addition, a mouse model of diabetes was established, which included a lincRNA-EPS knockout group and a lincRNA-EPS high expression group. Blood vessel samples from the mice were examined to determine the degree of calcification. The levels of inflammatory factors in serum were also detected. The VSMCs transfected with lincRNA-EPS overexpression vector exhibited less osteoblastic differentiation and migration and significantly lower levels of Wnt pathway-associated proteins than those transfected with empty control. Furthermore, the in vivo experiments revealed that the overexpression of lincRNA-EPS significantly reduced VC in diabetic mice. Therefore, on the basis of these findings, it is suggested that lincRNA-EPS overexpression may provide a novel and effective method for the treatment of VC in patients with diabetes.