Acute myocardial infarction (AMI) has been an economic and health burden in most countries around the world. Reperfusion is a standard treatment for AMI as it can actively restore blood supply to the ischemic site. However, reperfusion itself can cause additional damage; a process known as cardiac ischemia/reperfusion (I/R) injury. Although several pharmacological interventions have been shown to reduce tissue damage during I/R injury, they usually have undesirable effects. Therefore, endogenous substances such as melatonin have become a field of active investigation. Melatonin is a hormone that is produced by the pineal gland, and it plays an important role in regulating many physiological functions in human body. Accumulated data from studies carried out in vitro, ex vivo, in vivo, and also from clinical studies have provided information regarding possible beneficial effects of melatonin on cardiac I/R such as attenuated cell death, and increased cell survival, leading to reduced infarct size and improved left-ventricular function. This review comprehensively discusses and summarizes those effects of melatonin on cardiac I/R. In addition, consistent and inconsistent reports regarding the effects of melatonin in cases of cardiac I/R together with gaps in surrounding knowledge such as the appropriate onset and duration of melatonin administration are presented and discussed. From this review, we hope to provide important information which could be used to warrant more clinical studies in the future to explore the clinical benefits of melatonin in AMI patients.