miRNAs confer genetic robustness by precisely regulating protein expression. Studies in invertebrate models support that miRNA regulation of developmental gene networks provides phenotypic reproducibility under genetic or environmental perturbations. Whether miRNAs ensure uniform phenotypes in vertebrate development is unclear, as most mammalian miRNA gene knockouts do not have embryonic defects. Using a multifaceted, single-cell resolution screen of zebrafish embryonic blood vessels, we found that TALEN and CRISPR/Cas9 mutagenesis of single and multi-gene endothelial-expressed miRNA families significantly altered natural phenotypic variation of vascular cells. Genome-wide analysis of endothelial miRNA target genes revealed that each miRNA functions in distinct specification and morphogenesis signaling networks. Upon pharmacological network perturbation, the vascular system becomes further sensitized to aberrant malformations with progressive loss of miRNA gene copies. Our data establish that miRNAs act individually or in concert with other members in the phylogenetic family to faithfully reproduce tissue architecture complexity and to stabilize specific phenotypes in the face of variable perturbations. These discoveries demystify the cryptic function of miRNA-gene regulation in vertebrate development, and establishes it as a pivotal mechanism in defining an individual’s phenome and disease susceptibility.