Background and Purpose The molecular mechanisms responsible for atherogenesis have not been fully elucidated. The intraplaque endothelium dysfunction and associated inflammation are believed to contribute to the progression of atherosclerosis. This study aims to uncover molecular drivers of atherosclerotic cardiovascular disease and then develop therapeutic strategies for the disease. Methods The expression of zinc-finger transcription factor Snail in human and mouse atherosclerotic plaques was assessed using immunostaining, LacZ reporter mouse line and single-cell RNA-sequencing. The functional role and underlying mechanisms of endothelium-derived Snail in driving atherosclerosis was determined using the canonical and accelerated models of atherosclerosis developed in the endothelial cell (EC)-specific Snail-inducible deleted mice with the ApoE-/- background. An orally bioavailable small-molecule inhibitor of Snail was developed using the docking algorithm analysis and chemical structural optimization, and the anti-atherosclerotic effects of the compound were evaluated in mice. Results Snail is activated in ECs in both human and mouse atherosclerotic plaques, and its expression is positively correlated with disease severity. EC-specific Snail deletion in ApoE-/- mice reduces intraplaque endothelium dysfunction, inflammation and lipid uptake in tandem with enhanced plaque stability. Mechanistically, Snail deletion decreases histone acetylation on Ccl5 and Cxcl10 promoters, thereby decreases CCL5/CXCL10-driven vascular damage and inflammation. Administration with recombinant CXCL10 protein could efficiently restore atherogenesis in Snail-deleted mice. The orally bioavailable small-molecule inhibitor of Snail exhibits a potent anti-atherosclerotic effect in ApoE-/- mice. Conclusions These results reveal that Snail plays an essential role in atherogenesis and pharmacological targeting of Snail may provide therapeutic benefits against atherosclerotic cardiovascular disease.