Human heart regeneration is one of the most critical unmet clinical needs at a global level. Muscular regeneration is hampered both by the limited renewing capacity of adult cardiomyocytes and the onset of cardiac fibrosis, resulting in reduced compliance of the tissue. Large animals have proven to be ideal models for testing pluripotent stem cell strategies for heart regeneration, but unravelling specific approaches to drive cell migration to the site of injury and inhibit subsequent fibrosis have been elusive. Herein, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart bio-mimics, we uncover the coordinated modes of action in human ventricular progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 signalling directs cellular migration to sites of cardiac injury. Cardiac fibrosis is targeted by repulsion of activated fibroblasts regulated by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. Injection of human cardiac progenitors into porcine hearts following radiofrequency ablation injury proved their homing and ability to generate a remuscularized scar in vivo. After myocardial infarction, transplanted progenitors enhance cardiac function equally to differentiated cardiomyocytes, but with significant lower risk of graft-associated ventricular arrhythmias and increased numbers of blood vessel networks. Our study demonstrates that inherent developmental programs within cardiac progenitors are sequentially activated in the context of disease, allowing the cells to sense and counteract injury. As such, they may represent an ideal bio-therapeutic for functional heart rejuvenation.