<p>Physical activity is widely accepted for its myriad health benefits, serving as protective mechanisms against many chronic diseases. At the molecular level, exercise exerts its beneficial effects partly through the release of myokines, particularly irisin, which is cleaved from its precursor fibronectin type III domain–containing protein 5 and subsequently secreted from skeletal muscles in response to exercise. Irisin plays a pivotal role in metabolic regulation by inducing the browning of white adipose tissue, enhancing energy expenditure, attenuating insulin resistance, and improving systemic metabolism. In addition to its metabolic functions, irisin has received significant attention for its involvement in the regulation of several forms of programmed cell death such as apoptosis, ferroptosis, pyroptosis, and autophagy in recent years. The newfound interest stems from its potential to modulate cell survival and recycling mechanisms, positioning irisin as a promising chemical for treating a wide range of diseases characterized by aberrant cell death processes such as cardiovascular diseases, ischemia/reperfusion injury, and diabetes. This review therefore aims to collate and discuss the latest evidence on irisin’s role in programmed cell death regulation and exploring the implications of these effects for disease intervention. Furthermore, the review identifies the existing knowledge gaps, emphasizing the necessity of understanding irisin’s molecular mechanisms of action and the development of therapeutic applications to fully leverage its health-promoting potential.</p> Graphical Abstract <p></p>