Background and Objective. Exosomes secreted from mesenchymal stem cells (MSC) have demonstrated cardioprotective effects. This study examined the role of exosomes derived from MSC overexpressing CXCR4 for recovery of cardiac functions after myocardial infarction (MI). Methods. In vitro, exosomes from MSC transduced with lentiviral CXCR4 (Exo(CR4)) encoding a silencing sequence or null vector were isolated and characterized by transmission electron microscopy and dynamic light scattering. Gene expression was then analyzed by qPCR and Western blotting. Cytoprotective effects on cardiomyocytes were evaluated and effects of exosomes on angiogenesis analyzed. In vivo, an exosome-pretreated MSC-sheet was implanted into a region of scarred myocardium in a rat MI model. Angiogenesis, infarct size, and cardiac functions were then analyzed. Results. In vitro, Exo(CR4) significantly upregulated IGF-1α and pAkt levels and downregulated active caspase 3 level in cardiomyocytes. Exo(CR4) also enhanced VEGF expression and vessel formation. However, effects of Exo(CR4) were abolished by an Akt inhibitor or CXCR4 knockdown. In vivo, Exo(CR4) treated MSC-sheet implantation promoted cardiac functional restoration by increasing angiogenesis, reducing infarct size, and improving cardiac remodeling. Conclusions. This study reveals a novel role of exosomes derived from MSC(CR4) and highlights a new mechanism of intercellular mediation of stem cells for MI treatment.