Diabetes mellitus has substantial global implications and contributes to vascular inflammation and the onset of atherosclerotic cardiovascular diseases. However, translating the findings from animal models to humans has inherent limitations, necessitating a novel platform. Therefore, herein, we established an arterial model using a microphysiological system. This model successfully replicated the stratified characteristics of human arteries by integrating collagen, endothelial cells (ECs), and vascular smooth muscle cells. Perfusion via a peristaltic pump showed dynamic characteristics distinct from those of static culture models. High glucose, advanced glycation end products (AGEs), and interleukin-1 beta were employed to stimulate diabetic conditions, resulting in notable cellular changes and different levels of cytokines and nitric oxide. Additionally, the interactions between the disease models and oxidized low-density lipoproteins were examined. Finally, we investigated the potential therapeutic effects of metformin, atorvastatin, and diphenyleneiodonium. Metformin and diphenyleneiodonium mitigated high-glucose- and AGE-associated pathological changes, whereas atorvastatin affected only the morphology of ECs. Altogether, our arterial model represents a pivotal advancement, offering a robust and insightful platform for investigating cardiovascular diseases and their corresponding drug development. This article is protected by copyright. All rights reserved.