<p>Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation, fibrous tissue proliferation, and calcium deposition in the intima, contributing significantly to the mortality associated with cardiovascular disease, and the pathogenesis of AS is multifaceted. Recent studies have identified copper (Cu) overlap induced cuproptosis as a key mechanism underlying cellular dysfunction in AS. Cuproptosis impacts the function and survival of multiple cell types within AS lesions by several downstream pathways, and regulating cellular cuproptosis may be a very promising clinical treatment strategy. In this review, we explored the influence of key regulatory proteins and signaling pathways associated with copper homeostasis and cuproptosis in AS, and the potential regulators of cuproptosis in AS therapy, especially the endogenous metabolites, copper ionophore, Cu oxide nanoparticles and natural products, we also discuss emerging therapeutic strategies and offering insights into future developments and translational medicine or challenge by targeting cuproptosis in AS pathogenesis.</p> Graphical Abstract <p>Copper homeostasis imbalance significantly promotes cuproptosis in AS plaques. and regulating cuproptosis may be a new strategy for clinical treatment of atherosclerosis, such as copper chaperone proteins, copper ionophore, natural products endogenous metabolites and exogenous regulators.</p> <p></p>