Atherosclerotic vascular disease is the major cause of mortality in type 2 diabetes. This study sought to examine the effects of different receptor for advanced glycation end-products (RAGE)-targeted interventions in diabetic atherosclerosis. A diabetic atherosclerosis model was constructed in ApoE-/- mice by high-fat diet feeding combined with streptozotocin injection. Human umbilical vein endothelial cells were treated with high glucose and oxidized low-density lipoprotein. RAGE was inhibited via three strategies: overexpression of soluble RAGE (sRAGE), small interfering RNA (siRNA) or short hairpin RNA (shRNA)-mediated knockdown of RAGE, and pharmacological blockade using FPS-ZM1. RAGE inhibition suppressed systemic and vascular inflammation. RAGE inhibition elevated endothelial nitric oxide synthase levels and downregulated vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 expression to improve endothelial dysfunction. RAGE blockade improved lipid metabolism, resulting in decreased total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels while elevating high-density lipoprotein cholesterol concentrations. These effects were confirmed in both in vivo and in vitro models. RAGE inhibition mitigated aortic structural damage and lipid deposition in diabetic atherosclerotic mice. These protective effects were consistently observed across all three intervention strategies. Genetic and pharmacological RAGE inhibition alleviates diabetic atherosclerosis and represents a potential therapeutic target for diabetes-related macrovascular complications.