Fibrotic scarring is an intrinsic mechanism of the cardiac injury response in humans and other mammals, lacking significant regenerative potential in heart tissues.  In contrast, some vertebrates including zebrafish are capable of complete and scarless regeneration even after severe cardiac tissue damage.  The general opinion is that scarring limits regeneration and hence is a leading cause of morbidity in patients.  However, unifying mechanisms that prevent scarring and promote regeneration remain elusive.  Here, employing comparative transcriptional profiling coupled with genetic loss-of-function studies, we identify a single pathway, canonical Interleukin-11 (Il-11)/Stat3 signaling, as a global upstream regulator of regeneration and scarring in zebrafish.  We show that animals lacking Il-11 signaling display strongly impaired regeneration across diverse tissues and developmental stages, essentially resembling the non-regenerative phenotype of adult mammals.  By analyzing regeneration in the adult heart, we show that Il-11 acts to reprogram stromal cells to activate global and tissue-specific regenerative gene programs, and to broadly limit hallmarks of the adult mammalian scarring response.  Using lineage tracing and transgenic approaches, as well as human cells in culture, we show that IL-11 signaling in endothelial cells antagonizes pro-fibrotic transforming growth factor beta (TGF-β) signaling and endothelial-to-mesenchymal transition (EndoMT) limiting scarring, and allowing cardiomyocyte protrusion post cardiac injury.