Myocardial infarction, commonly known as heart attack, evolves from the rupture of unstable atherosclerotic plaques to coronary thrombosis and myocardial ischemia–reperfusion injury. A body of evidence supports a close relationship between the alterations following an ischemia–reperfusion injury-induced oxidative stress and platelet activity. Through their critical role in thrombogenesis and inflammatory responses, platelets are fully (totally) implicated from atherothrombotic plaque formation to myocardial infarction onset and expansion. However, mere platelet aggregation prevention does not offer full protection, suggesting that other antiplatelet therapy mechanisms may also be involved. Thus, the present review discusses the integrative role of platelets, oxidative stress, and antiplatelet therapy in triggering myocardial infarction pathophysiology.