Abstract: Cardiovascular diseases (CVDs) are one of the important causes of health risk and death. Atherosclerosis (AS) is considered to be the key pathological basis of persistent CVDs. AS is a chronic progressive inflammatory disease characterized by excessive lipid deposition, oxidative stress, inflammatory response, plaque formation and rupture, thrombosis and vascular calcification (VC). Vascular smooth muscle cells (VSMCs) are the core part of maintaining the normal structure of blood vessels and play a key role in the pathological process of AS. Their proliferation, migration, differentiation, senescence and death processes have an important impact on the progression of AS. The specific mechanism of VSMCs participating in AS has always been the focus of research in the cardiovascular field. In recent years, natural products have garnered considerable attention in the field of AS prevention and treatment, primarily due to their multi-target effects, low toxicity and side effects. However, there is still a lack of systematic review of natural compounds that alleviate AS by regulating the function of VSMCs. This article focuses on the core role of VSMCs in the progression of AS, and systematically reviews the natural compounds targeting VSMCs metabolism and their molecular regulatory mechanisms. By combing the relevant pharmacological activities and potential targets, the pathological function of VSMCs in AS is further elucidated, thereby providing an important theoretical basis for the development of novel and efficient AS treatment strategies.