Atherosclerosis (AS) is the main pathology underlying cardiovascular and cerebrovascular diseases. Dyslipidemia, inflammation, and oxidative stress are key factors in the development and progression of atherosclerosis. In many tissues, nicotinamide adenine dinucleotide (NAD+) levels and sirtuins activity decrease with age, and they are closely related to the pathological process of cardiovascular diseases, such as dyslipidemia and atherosclerosis. NAD+ supplementation or activation of sirtuins plays a role in preventing and treating cardiovascular diseases. Clinical trials in humans have indicated that drugs or strategies that increase NAD+ levels have potential effects in ameliorating dyslipidemia or atherosclerosis. Here, we attempt to depict the role of NAD+ and its metabolism in lipid metabolism, inflammation, and oxidative stress related to atherosclerosis, as well as the recent advances in the therapeutic applications in clinic.