Irisin, an exercise-induced myokine, exhibits elevated levels during physical activity, yet its role in modulating the unfolded protein response (UPR) remains poorly understood. This comprehensive review pioneers an in-depth examination of irisin-mediated endoplasmic reticulum (ER) stress mitigation across various diseases. We provide a nuanced characterization of irisin's molecular profile, biological activity, and significance as a skeletal muscle-derived cytokine analogue. Our discussion elucidates the complex interplay between exercise, irisin signalling, and metabolic outcomes, highlighting key molecular interactions driving salutary effects. Moreover, we delineate the UPR's role as a critical ER stress countermeasure and underscore irisin's pivotal function in alleviating this stress, revealing potential therapeutic avenues for disease management. Exercise-induced release of irisin ameliorates ER stress through AMPK phosphorylation during various diseases (Icon image source: www.flaticon.com ).