Vascular inflammation is responsible for many cardiovascular diseases and endothelial dysfunction is often the first trigger. Many factors can contribute to altering vascular homeostasis and despite that some risk factors cannot be changed, some lifestyle changes might dramatically improve vascular function. In this regard, physical activity has been identified as one of the most important interventions that can positively affect endothelial dysfunction. In recent years, the discovery of irisin, a novel myokine with pleiotropic effects, has caught the attention of many researchers. This review summarizes the most relevant intervention trials, evaluating irisin modifications in subjects with or without cardiovascular risk factors assigned to physical activity programs, to improve cardiovascular risk markers.