Endothelial dysfunction plays a pivotal role in the pathogenesis of various cardiovascular diseases (CVDs), including atherosclerosis, hypertension, heart failure, stroke, and peripheral artery disease. It disrupts vascular homeostasis, leading to reduced nitric oxide (NO) bioavailability, increased oxidative stress, and chronic inflammation, all of which collectively drive vascular damage, atherosclerotic plaque formation, and thrombosis. Additionally, shear stress-induced alterations in blood flow patterns, particularly disturbed flow (d-flow), aggravate endothelial dysfunction. Furthermore, the endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells acquire mesenchymal-like properties, contributes to vascular remodeling and accelerates CVD progression.This review explores the significant role of epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs (ncRNAs), which serve as critical regulators of endothelial function in response to shear stress in endothelial dysfunction and the development of atherosclerosis. Furthermore, we discuss the pivotal role of endothelial dysfunction in cardiovascular and metabolic diseases, emphasizing the need for innovative therapeutic strategies beyond conventional treatments. In particular, we highlight the endothelial-protective mechanisms of emerging pharmacological agents, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, along with supporting clinical evidence demonstrating their efficacy in improving endothelial function and reducing cardiovascular risk.