Human pluripotent stem cell-derived cardiomyocytes are emerging as a powerful platform for cardiovascular drug discovery and toxicology. However, standard 2D cultures are typically immature, which limits their capacity to predict human biology and disease mechanisms. To address this problem, we have recently developed a high-throughput bioengineered human cardiac organoid (hCO) platform, which provides functional contractile tissue with biological properties similar to native heart tissue including mature, cell cycle-arrested cardiomyocytes. Here, we take advantage of the screening capabilities of our mature hCO system to perform functional screening of 105 small molecules with pro-regenerative potential. Our findings reveal a surprising discordance between the number of pro-proliferative compounds identified in our mature hCO system compared with traditional 2D assays. In addition, functional analyses uncovered detrimental effects of many hit compounds on cardiac contractility and rhythm. By eliminating compounds that had detrimental effects on cardiac function, we identified two small molecules that were capable of inducing cardiomyocyte proliferation without any detrimental impacts on function. High-throughput proteomics on single cardiac organoids revealed the underlying mechanism driving proliferation, which involved synergistic activation of the mevalonate pathway and a cell cycle network. In vivo validation studies confirmed that the mevalonate pathway was shut down during postnatal heart maturation in mice and statin-mediated inhibition of the pathway inhibited proliferation and heart growth during the neonatal window. This study highlights the utility of human cardiac organoids for pro-regenerative drug development including identification of underlying biological mechanisms and minimization of adverse side-effects.