The composition and biological activity of donor cells is largely determined by the exosomes they secrete. In this study, we isolated exosomes from young (Young-Exo) and aged (Age-Exo) mesenchymal stem cells (MSCs) and compared their regeneration activity. Young Exo MSCs were more efficient than Aged-Exo at promoting the formation of endothelial tube, reducing fibrosis, and inhibiting apoptosis of cardiomyocytes ; and improving cardiac structure and function in the hearts of rats following myocardial infarction (MI). MicroRNA sequencing and polymerase chain reaction (PCR) analysis revealed that miR-221-3p was significantly down-regulated in Aged-Exo. The aged MSCs were rejuvenated and their reparative cardiac ability restored when miR-221-3p was overexpressed in Aged-Exo. The protective effect was lost when miR-221-3p expression was knocked down in Young-Exo. These effects of miR-221-3p were achieved through enhancing Akt kinase activity by inhibiting phosphatase and tensin homolog (PTEN). In conclusion, exosomal miR-221-3p secreted from Aged MSCs attenuated the function of angiogenesis and promoted survival of cardiomyocytes. Up-regulation of miR-221-3p in aged MSCs improved their ability of angiogenesis, migration and proliferation, and suppressed apoptosis via the PTEN/Akt pathway.