Infantile hemangioma (IH), the most common vascular tumor of infancy, relies on hemangioma stem cells (HemSCs) to drive pathological vasculogenesis during the proliferating phase. While beta-blockers are currently first-line treatment for IH, resistance and rebound growth necessitates novel strategies. Here, we identify histone deacetylase inhibitors (HDACi) as a potential epigenetic drug for IH. The pan-HDAC inhibitor SAHA significantly suppresses in vivo vasculogenesis in a murine IH model. Mechanistically, SAHA selectively blocks the differentiation of HemSCs into pericytes by destabilizing NOTCH3 protein through acetylation-primed ubiquitination and proteasomal degradation, thus disrupting perivascular support which is indispensable for IH vasculogenesis. Furthermore, the blockade of pericyte differentiation by SAHA synergizes with propranolol, which inhibits endothelial differentiation of HemSCs, in a complementary manner. Additionally, SAHA promotes adipogenic differentiation of HemSCs and accelerates IH involution. Collectively, our work highlights the clinical significance of cell fate determination during IH progression, and establishes HDAC inhibition as a novel therapeutic option for IH through targeting pericyte differentiation of HemSCs, which provides a promising enhancement to current treatment strategies of refractory IH.