Heart failure due to Myocardial Infarction (MI) remains the leading cause of death worldwide due to the inability of myocardial tissue to regenerate following infarction. Current therapies could only retard the progression of disease, but fails to bring functional improvement and cardiac regeneration. The present study analyzes the potentials of Poly(glycerol sebacate)/Fibrinogen (PGS/Fib) core/shell fibers as a structural support and initial entrapment of cells in an in vivo porcine model using echocardiography, histology, and immunohistochemistry. The echocardiography results showed the increased ejection fraction (EF) in PGS/Fib/VEGF/Cells compared with MI controls. The percentage increase in the End Diastolic Volume (EDV) dimension from post MI period to 4 weeks follow-up was the least in PGS/Fib/VEGF/Cells groups compared with MI and cell control group proving that the PGS/Fib/VEGF/Cells group restored the left ventricle (LV) function after MI, evident from the improvement in EF and prevention of LV enlargement. Further, immunohistochemistry results demonstrated that most of the transplanted mesenchymal stem cells (MSCs) within the PGS/Fib/VEGF scaffolds expressed cardiac marker proteins troponin and actinin and endothelial cell marker protein CD31 indicating differentiation of human bone marrow MSCs into cardiac cells and endothelial cells. The developed nanofibrous cardiac patch PGS/Fib/VEGF/Cells provides both functional and structural integrity to the infarcted myocardium and also serves as a suitable matrix for the entrapment of MSCs in clinical applications for cardiac tissue engineering.