Physical inactivity is a major risk factor for cardiovascular diseases. Regular exercise is considered a safe, simple, yet efficient strategy to reduce cardiovascular risk factors, prevent cardiovascular diseases and improve cardiovascular health. Exercise acts as a “polypill” for cardiovascular disease prevention and our body has an endogenous “medkit” with unlimited refills of this marvelous polypill. The mechanisms of exercise-induced cardiovascular health include alleviating oxidative stress and inflammation, improving cardiovascular insulin sensitivity and metabolism via activating Akt-eNOS “survival signaling” to reduce cardiovascular susceptibility to injury, in which the improvement of mitochondrial function plays a key role in exercise-induced cardiovascular health effects. Recent studies have shown that exerkines that are secreted from multiple tissues in response to exercise orchestrate multi-organ cross-talk in exercise-induced cardiovascular benefits. Clinically, exercise intervention has become a fundamental strategy in cardiac rehabilitation in recent years. This review highlights the challenges in elucidating the mechanisms underlying exercise-improved cardiometabolic health and perspectives on developing personalized and precise exercise prescription for the prevention and management of cardiovascular diseases.