Nidogen-1 (NID1) is a sulfated monomeric glycoprotein consisting of three globular domains: G1, G2 and G3 and with many epidermal growth factor repeats. It is an underinvestigated ECM basement membrane protein that is mostly recognized as a linker protein of COL4 and LAM. It has been suggested to play a role in angiogenesis, hepatic regeneration, and regenerative axon growth and guidance. Our research has demonstrated a potential cardiogenic effect of NID1 on differentiating pluripotent stem cells. We were further able to demonstrate that NID1 attenuates the apoptotic effect of hypoxia in cardiomyocytes and pancreatic beta cells via the αvβ3 integrin and beneficially modulates immune responses in vitro. We showed that NID1 significantly increases heart function and angiogenesis, while reducing fibrosis, in a mouse postmyocardial infarction model; therefore, demonstrating the protective and regenerative potential of NID1 in ischemic conditions.