A sedentary lifestyle, low levels of physical activity and fitness, poor dietary patterns, and psychosocial stress are strongly associated with increased morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD). Conversely, engaging in regular physical activity, maintaining optimal fitness levels, adhering to a heart-healthy dietary pattern, effectively managing body weight, ensuring adequate sleep, implementing stress-reduction strategies, and addressing psychosocial risk factors are associated with a reduced risk of ASCVD. This comprehensive review synthesizes current evidence from large observational studies and randomized controlled trials on lifestyle factors as determinants of ASCVD health. It also briefly reviews mechanistic insights into how factors such as low shear stress, increased reactive oxygen species production, chronic inflammation, platelets and coagulation activation, endothelial dysfunction, and sympathetic hyperactivity contribute to the initiation and exacerbation of ASCVD risk factors. These include obesity, hyperglycemia, type 2 diabetes, hypertension, and dyslipidemia, subsequently leading to the development and progression of atherosclerosis, ultimately resulting in chronic ASCVD or acute cardiovascular events. To bridge the translational gap between epidemiologic and trial-based evidence and clinical practice, practical recommendations are summarized to facilitate the translation of scientific knowledge into actionable interventions to promote ASCVD health. Acknowledged is the gap between the evidence-based knowledge and adoption within healthcare systems, which remains a crucial objective in advancing cardiovascular health at the population level.