The cardiovascular diseases (CVDs) are the most prevalent causes of death in the world with limited treatment of severe myocardial injury and end stage heart failure. According to the recent experimental and early clinical data, the transplantation of mitochondria, that is, the direct delivery of functioning mitochondria to the inflicted myocardium, may potentially restore bioenergetics, minimize oxidative stress and enhance cardiac functions. This systematic review, summarizes both preclinical and clinical evidence demonstrating the effectiveness, mechanism, and translational issues of mitochondrial transplantation in the heart. Based on the PRISMA-directed methodology the literature reviews are relevant, and were identified in PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov where there was consistent improvement in the restoration of adenosine triphosphate (ATP), reduction in oxidative harm, increased left ventricular ejection fraction (LVEF), and structural recovery in both small and large animal models and in pediatric trials. Mitochondrial internalization through mitochondrial macropinocytosis, followed by fusion with native mitochondria, and mitophagy and biogenesis signaling are proposed to happen as suggested by mechanistic findings. Although the result is promising, there is still a challenge on methods of delivery, optimization of dosage, long term incorporation, and classification by the regulatory authorities. This paper concludes that mitochondrial transplantation is a new paradigm of subcellular regenerative therapy and it should be studied by standardized procedures and controlled clinical trials to prove the safety and efficacy