Atherosclerosis is a chronic inflammatory disease that contributes significantly to several cardiovascular diseases, such as peripheral arterial and coronary artery disease. Its origin involves the thickening of the arteries due to the formation of plaques, resulting in varying degrees of obstruction of blood flow. In recent years, advances in molecular biology and microbiome science have highlighted the complex interplay between genetic and environmental factors in the progression of atherosclerosis. In this context, Apolipoprotein E (APOE), the gut microbiota, and their metabolites are shown to be central elements of a functional axis that connects the intestine to the vascular endothelium. APOE isoforms (especially APOE4) play a key role not only in lipid metabolism but also in regulating systemic inflammation and gut microbiota composition. The APOE4 genotype is associated with a greater susceptibility to the development of atherosclerotic plaques, partly due to its connection with microbial imbalances and increased production of metabolites. One of them is trimethylamine N-oxide (TMAO), a pro-inflammatory compound that contributes to endothelial dysfunction and the formation of foamy cells. Additionally, gut microbiome influences processes such as lipid absorption, reverse cholesterol transport, and bile acid metabolism. When dysbiosis is favored by the APOE4 genotype, there is an impairment in the production of beneficial metabolites, such as short-chain fatty acids, leading to increased intestinal permeability and the translocation of lipopolysaccharides into the bloodstream, thereby intensifying chronic inflammation. Therefore, bidirectional crosstalk is evidenced between APOE, the gut microbiome, and atherosclerosis. This axis not only broadens our understanding of the disease mechanisms but also offers innovative therapeutic opportunities, particularly dietary interventions aimed at restoring intestinal homeostasis and controlling vascular inflammation.