One of the most common causes of global death is cardiovascular disease. Using mesenchymal stem cells (MSCs) therapy for treating cardiovascular diseases has become an emerging knowledge in regenerative medicine. Some challenges that have limited MSC therapy practical application, including cell harvesting difficulty, ectopic transplantation, spontaneous differentiation to cartilage and bone, and possible immune responses following transplantation. MSCs release extracellular vesicles and biologically active molecules such as growth factors, chemokines, and cytokines named secretomes. Recent studies have shown secretome administration could replace MSC transplantation. The secretome of MSCs plays a crucial role in controlling inflammatory reactions, enhancing tissue reperfusion by stimulating angiogenesis and vasculogenesis, preventing apoptosis and fibrosis development, and fostering the proliferation and differentiation of cardiac stem cells. This review aims to discuss the current knowledge of MSC secretome application in cardiac regenerative medicine and introduces the possible approaches to improve cardiac recovery outcomes through utilizing secretome in the clinic.