Unlike adult mammals, zebrafish (Danio rerio) are able to naturally regenerate their heart. We have used the cryoinjury model of myocardial infarction (MI) in the zebrafish to study heart regeneration. In this model, a copper filament is pre-cooled in liquid nitrogen and applied to the apex of the ventricle. Cryoinjury triggers in tissue necrosis and results in a severe apoptotic response and the generation of a scar. A key mechanism in zebrafish heart regeneration is the activation of the epicardium, leading to the establishment of a supporting scaffold for newly formed cardiomyocytes, angiogenesis and cytokine secretion. Neuropilins (NRPs) are cell surface co-receptors mediating functional signalling of kinase receptors for cytokines known to play critical roles in zebrafish heart regeneration, including Platelet-derived growth factor (PDGF), Vascular endothelial growth factor (VEGF), and Fibroblast growth factor (FGF). Herein, we investigated the role of neuropilins in the response of the zebrafish heart to cryoinjury and its subsequent regeneration. Zebrafish have four neuropilin isoforms, nrp 1a, 1b, 2a and 2b. We found that all isoforms were upregulated following cardiac cryoinjury and were strongly expressed by the activated epicardium. A nrp1a mutant, coding for a truncated, non-functional protein, shows a significant delay in heart regeneration in comparison to wild type fish and displays a lasting collagen deposition. Importantly, epicardial cells from nrp1a mutant zebrafish heart explants display an impaired response to activation by cryoinjury and have a lower re-expression of the developmental gene Wilms’ tumour 1. Moreover, the revascularisation of the heart is compromised: less new vessels are seen invading the injured region of the mutant hearts in comparison to wild-type. These results identify a key role for Nrp1 in zebrafish heart regeneration, mediated through epicardial activation and migration and revascularisation of the damaged area of the heart.