Heart failure remains a leading cause of morbidity and mortality worldwide. Despite advances in medical management and device-based therapies, there is no cure for the damaged heart. The traditional therapeutic options for patients with heart failure, such as drugs, surgeries, and transplantation, have limitations and risks, leading to the need for innovative novel therapies. Clinical and ... [Show full abstract] preclinical studies have shown that extracellular vesicles (EVs) secreted by transplanted cells are more effective than direct stem cell transfer in the mechanisms involved in cardiac regeneration following ischemia. EVs have gained increasing attention as potential mediators of cardiac repair and regeneration. Preclinical studies have demonstrated the regenerative effect of EVs from a variety of cardiac cell types, including cardiac progenitor cells, mesenchymal stem cells, and iPS cells. Upon EV administration, the functional capacity of the heart improved, myocardial hypertrophy reduced, and necrosis resulted in a lesser degree. This indicates that EVs’ ability to transport proteins, lipids, non-coding RNAs, and other biologically active factors plays a vital role in promoting cardiac restoration. At present, several clinical trials are exploring the therapeutic potential of EVs in heart regeneration approaches.