The association between sedentary behavior or physical inactivity and risk for developing vascular aging, Cardiovascular (CVD) or Coronary Artery Disease (CAD) as well as developing risk factors for the disease is high. The health benefits of increasing physical activity and reducing sedentary behavior using various recommended intervention strategies are a field that warrants further research. While genetic risk factors for CVD have been well documented, emerging evidence has linked epigenetic mechanisms (i.e., heritable changes to gene expression that are not from differences in the genetic code) with many CVDs. Epigenetic mechanisms are regulated by many factors including physical activity, tobacco smoke and diet. Recent evidence provides support for the theory of epigenetic inheritance in which epigenetic alteration in gametes are transferable from parents to offspring. We must not only understand accelerated vascular aging and CVD risk factors and their regulatory role in prevention, management and diagnosis of CVDs but also practice protective measures that include lifestyle (i.e., physical activity, diet, abstinence of tobacco smoke) and epigenetic influence would play a significant role on cardiovascular health. This review examines the interplaying role of sedentary behavior or physical inactivity, tobacco smoke, and epigenetics in CVD risk. Specifically, we report the association between epigenetics and cardiovascular diseases as well as the interplay of epigenetic mechanisms in cardiovascular diseases and maternal smoking and secondhand smoke that have adverse effects on health of newborns, childhood obesity and off-spring developing smoking habits, asthma, and arterial stiffness.