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Introduction: Human iPSC derived cardiomyocytes (iPSC-CMs) have been proved to be a promising method to treat the heart failure. Multiple clinical studies including one in our group are ongoing around the world. Due to the diffusion limit, so far it is difficult to prepare viable cardiac tissue with high thickness. We hypothesized that by using multilayer fiber sheets and enhanced perfusion system, viable and thick cardiac tissue could be obtained for improved therapeutic effect for treating myocardial infarction. Method and Results: PLGA fiber sheet with multilayer and high porosity (30.61% ± 1.85%, n = 4) was fabricated for iPSC-CMs penetration and organization. A low-shear stress perfusion system was developed to promote the oxygen diffusion in the thick tissue. At day 5, multilayer cardiac tissue showed compact structure with thickness of 878.64 ± 193.45 μm (n = 4) and viability of 85.32 % ± 6.75 % (n = 4). Compared with the single layer tissues, the multilayer cardiac tissues demonstrated improved contractile properties and secretion of angiogenesis factors: VEGF, HGF and TGF-β1. When used for treating rat with myocardial infarction, multilayer group showed significantly improved left ventricular ejection fraction (0 vs. 4 week: 39.1 ± 4.6 % vs. 52.3 ± 7.8 %, n=8, p = 0.0029), whereas the control group showed no significant change (0 vs. 4 week: 40.6 ± 5.4 % vs. 44.9 ± 4.1 %, n=8, p = 0.37). The staining on sliced heart confirmed the survival of transplanted cells in large area. Moreover, the multilayer group showed significantly lower fibrosis at the border zone than the control group (10.8 % ± 3.1 % vs. 16.4 % ± 5.9 %, n=7, p=0.024). There are no significant differences in cell diameter and capillary density in border zone between two groups. Both groups showed no significant inflammatory reactions (CD68). Conclusion: By using multilayers fiber sheet and enhanced perfusion system, viable and thick iPSC-cardiac tissue could be obtained with enhanced features over the single layer cardiac tissue such as contractility and secretion. While used for transplantation, the multilayers cardiac tissue demonstrated improved therapeutic effect for treating myocardial infarction, holding high potential for future clinical applications.