Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio-temporal control of proliferative induction, and the need to coordinately reprogram multiple regulatory pathways to overcome the strict post-mitotic state of human adult cardiomyocytes. To address this unmet therapeutic need, a combinatorial miRNA interference screen is performed specifically targeting cardiac-predominant miRNAs regulating key aspects of cardiomyocyte mitotic induction to cell-cycle completion in neonatal rat cardiomyocytes. In doing so combinatorial interference of miRNA-1a and miRNA-15b (LNA-1a/15b) is identified as drivers of adult cardiomyocyte proliferation. Due to miRNA-1a/15b function on multiple processes modulating adult cardiomyocyte mitosis, its inhibition augmented adult cardiomyocyte cell-cycle completion and daughter cell formation, and improved contractility in 3D human cardiac organoids, and in a mouse model of ST-segment elevation myocardial infarction. Due to the cardiac-restricted pattern of miRNA-1a/15b expression, this strategy provides a feasible means for specific cardiomyocyte proliferative induction with minimal risk of neoplasm formation and off-target toxicity. The approach further highlights an underutilized therapeutic strategy for simultaneous co-regulation of multiple disease pathways through combinatorial interference of miRNAs.