Homocysteine (Hcy), a metabolite of methionine in the human body, is associated with the pathogenesis of various diseases. Hyperhomocysteinemia (HHcy) is an independent risk factor for the onset and development of systemic atherosclerosis, cardiovascular disease (CVD), and stroke. The inflammatory reactions, lipid metabolism abnormalities, and coagulation dysfunction induced by Hcy seriously affect the normal structure and function of blood vessels, thereby accelerating the progression of atherosclerosis. Supplementation with folic acid and B vitamins can effectively reduce blood Hcy levels in patients with HHcy. This article reviews the mechanism by which HHcy accelerates the progression of CVD, providing new insights for clinical prevention and treatment of HHcy.