Multi-organ animals, such as vertebrates, require the development of a closed vascular system to ensure the delivery of nutrients to, and the transport of waste from, their organs. As a result, an organized vascular network that is optimal for tissue perfusion is created through not only the generation of new blood vessels but also the remodeling and maintenance of endothelial cells via apoptotic and cell survival pathways. Here, we show that UBIAD1, a vitamin K2/menaquinone-4 biosynthetic enzyme, functions cell-autonomously to regulate endothelial cell survival and maintain vascular homeostasis. From a recent vascular transgene-assisted zebrafish forward genetic screen, we have identified a ubiad1 mutant, reddish/reh, which exhibits cardiac edema as well as cranial hemorrhages and vascular degeneration owing to defects in endothelial cell survival. These findings are further bolstered by the expression of UBIAD1 in human umbilical vein endothelial cells and human heart tissue, as well as the rescue of the reh cardiac and vascular phenotypes with either zebrafish or human UBIAD1. Furthermore, we have discovered that vitamin K2, which is synthesized by UBIAD1, can also rescue the reh vascular phenotype but not the reh cardiac phenotype. Additionally, warfarin-treated zebrafish, which have decreased active vitamin K, display similar vascular degeneration as reh mutants, but exhibit normal cardiac function. Overall, these findings reveal an essential role for UBIAD1-generated vitamin K2 to maintain endothelial cell survival and overall vascular homeostasis; however, an alternative UBIAD1/vitamin K-independent pathway may regulate cardiac function.