The aim of the present study is to explore the possible mechanism that may have ameliorative effect of liraglutide (Lira) on diabetic lower extremity vascular stenosis.A diabetic rabbit model of lower extremity stenosis was established and treated with Lira. The intimal hyperplasia of the lower extremity and the oxidative stress level of vascular tissue were observed and examined. Vascular smooth muscle cells (VSMCs) induced by high glucose (HG) were treated with Lira, and RCAN1 overexpressing plasmid was constructed to transfect VCMCs.Lira treatment showed its association in significantly improving the hyperplasia of the intima, the level of oxidative stress, and the level of homeostasis model assessment of insulin resistance (HOMA-IR) in rabbits induced by diabetes and lower limb stenosis. In addition, Lira treatment reduced the elevated expression of RCAN1 in vascular tissues induced by diabetes. Not only could Lira treatment inhibit the increase of ROS level, proliferation and migration of VSMCs induced by HG, but reduce the expression of PCNA, MMP-9 and collagen I induced by HG. Overexpression of RCAN1 in VSMCs counteracted the effect of Lira, suggesting that Lira affected the proliferation and migration of VSMCs by regulating RCAN1.Our findings have important implications for Lira to exert beneficial outcomes in reducing excessive neointimal formation after lower extremity vascular injury in diabetic rabbits via the regulation of RCAN1.