Astrocytes are crucial for central nervous system (CNS) development and function, with their differentiation being stringently controlled by epigenetic mechanisms, such as histone modifications. Enhancer of Zeste Homologue 2 (EZH2), a histone methyltransferase, is essential for the suppression of gene expression. However, the role of EZH2 in astrocyte early morphogenesis has remained unclear. Using an astrocyte-specific Ezh2 knockout (cKO) mouse model, we examined the effects of EZH2 deletion on astrocyte morphogenesis, blood-brain barrier (BBB) integrity and neurodevelopment. Loss of EZH2 led to increased glial fibrillary acidic protein (GFAP) expression, altered astrocyte morphology and reduced coverage of astrocytic endfeet on blood vessels, compromising BBB integrity. Vascular abnormalities, characterised by increased vascular density and smaller vessel diameter, mirrored compensatory changes seen in moyamoya disease. RNA-sequencing and ChIP-seq identified Ddn as a key upregulated gene in Ezh2