In humans, new-born infants have the ability to regenerate their heart during early life. This is modelled in the mouse, where regenerative capacity is maintained for the first week after birth but lost thereafter. Reactivation of this process holds great therapeutic potential, however, the molecular pathways that might be targeted to extend neonatal regeneration remain elusive. Here, we explore a role for hypoxia and HIF signalling on the regulation of epicardial activity which is essential for heart development and the response to injury. Hypoxic regions were found in the epicardium from mid-gestation, associating with HIF1α and HIF2α, and expression of the epicardial master regulator Wilms’ tumour 1 (WT1). Epicardial deletion of Hif1a reduced WT1 levels, leading to impaired coronary vasculature. Moreover, targeting of the HIF degradation enzyme PHD through pharmacological inhibition with clinically approved drugs or epicardial-specific deletion stabilised HIF and promoted WT1 activity ex vivo. A combination of genetic and pharmacological stabilisation of HIF during neonatal heart injury led to prolonged epicardial activation, increased vascularisation, augmented infarct resolution and preserved function beyond the 7-day regenerative window. Together, these findings suggest pharmacological modulation of HIF signalling may represent a viable therapeutic strategy for treating ischaemic heart disease.