Oxygen supplementation is potentially harmful in patients with acute coronary syndrome as it may lead to hyperoxia-induced coronary vasoconstriction. This phenomenon may deteriorate the already poor coronary perfusion. The exact physiology mechanisms of how hyperoxia causes vasoconstriction are still not fully elucidated. Some hypotheses were proposed, among others: 1) reduced nitric oxide (NO) bioavailability due to increased reactive oxygen species (ROS) generation; 2) hyperoxia-induced ATP-sensitive potassium channel closure; 3) activation of smooth muscles’ oxygen-sensitive calcium channel; 4) increased endothelin-1 release; and 5) increased production of 20-hydroxyeicosatetraenoic acid (20-HETE). A decent understanding of this phenomenon will aid in more awareness and better clinical management.