Background <p>Given the limited efficacy of available anti-angiogenic therapies in esophageal squamous cell carcinoma (ESCC), there is a need to explore new strategies to target this crucial tumour-promoting process. Emerging evidence suggests that epigenetic dysregulation, including histone deacetylation, may contribute to aberrant pro-angiogenic signalling. Therefore, we investigated whether histone deacetylase (HDAC) 3 and HDAC8-mediated hypoacetylation contribute to the silencing of anti-angiogenic genes angiopoietin-like 1 (<i>ANGPTL1)</i> and cluster of differentiation (<i>CD36)</i>, thereby promoting angiogenesis in ESCC.</p> Methods <p>ESCC cell lines and clinical tissues were analysed for the expression of <i>CD36</i>,<i> ANGPTL1</i>, vascular endothelial growth factor (<i>VEGF</i>), <i>HDAC3</i> and <i>HDAC8</i> and for histone acetylation markers histone H3 lysine 9 acetylation (H3K9ac) and histone H4 lysine 16 acetylation (H4K16ac) using qRT-PCR and immunoblotting. Functional angiogenesis was assessed through in vitro human umbilical vein endothelial cell (HUVEC) tube formation, ex vivo rat aortic ring assays, and endothelial migration (wound healing/Trans well) following interventions with suberoylanilide hydroxamic acid (SAHA) treatment, HDAC3 siRNA knockdown, or <i>CD36</i> overexpression.</p> Results <p>In ESCC tissues and cell lines, expression of <i>CD36</i> and <i>ANGPTL1</i> was downregulated, while <i>HDAC3</i> and <i>HDAC8</i> were upregulated, correlating with reduced levels of H3K9ac and H4K16ac. The HDAC inhibitor SAHA partially restored histone acetylation, significantly upregulated <i>CD36</i> and A<i>NGPTL1</i>, suppressed <i>VEGF</i>, and reduced angiogenesis in both in vitro and ex vivo models. Furthermore, knockdown of <i>HDAC3</i> produced a significant anti-angiogenic effect, comparable to the effect of <i>CD36</i> overexpression. In both cases, conditioned media from the modified cells impaired endothelial cell migration and tube formation.</p>