Physical inactivity is one of the leading modifiable risk factors for global mortality, with an estimated 20% to 30% increased risk of death compared with those who are physically active. The “behavior” of physical activity (PA) is multifactorial, including social, environmental, psychological, and genetic factors. Abundant scientific evidence has demonstrated that physically active people of all age groups and ethnicities have higher levels of cardiorespiratory fitness, health, and wellness, and a lower risk for developing several chronic medical illnesses, including cardiovascular disease, compared with those who are physically inactive. Although more intense and longer durations of PA correlate directly with improved outcomes, even small amounts of PA provide protective health benefits. In this state-of-the-art review, the authors focus on “healthy PA” with the emphasis on the pathophysiological effects of physical inactivity and PA on the cardiovascular system, mechanistic/triggering factors, the role of preventive actions through personal, education/environment, and societal/authoritative factors, as well as factors to provide guidance for caregivers of health promotion regarding PA. Sustainable and comprehensive programs to increase PA among all individuals need to be developed and implemented at local, regional, national, and international levels to effect positive changes and improve global health, especially the reduction of cardiovascular disease.