<p>Atherosclerosis is a chronic inflammatory disease influenced by host–microbiota interactions beyond traditional risk factors. Microbial communities in the oral cavity, gut, and blood contribute to vascular dysfunction through metabolic and immune mechanisms, yet an integrated perspective across these compartments remains lacking. This narrative review synthesizes current evidence on the distinct and interconnected roles of oral, gut, and blood microbiotas in atherosclerosis pathogenesis. We critically evaluate key microbial metabolites, trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids, and their mechanisms of host metabolic and immune modulation. We also examine cross-compartment interactions, emerging multi-omics approaches, and the translational potential of microbiota-targeted interventions. Oral pathogens promote systemic inflammation and endothelial activation. Gut-derived metabolites such as TMAO exacerbate foam cell formation and impair reverse cholesterol transport, whereas SCFAs exert protective effects via immune modulation and gut barrier maintenance. Emerging evidence suggests that blood microbial components contribute to vascular inflammation, though methodological challenges remain. Multi-omics integration (metagenomics, metabolomics, host genomics) reveals interconnected metabolic networks linking microbial activity to atherosclerosis. Microbiota-targeted strategies, including dietary modulation, TMA lyase inhibitors, and probiotics, show promise for risk stratification and therapeutic intervention. The human microbiota regulates atherosclerosis through immunometabolic metabolites, offering promising biomarkers and therapeutic targets. However, clinical translation requires addressing interindividual variability, establishing causality, and standardizing methodologies. This review provides an integrated framework for leveraging microbiota–host interactions in precision cardiovascular medicine.</p>