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Atherosclerosis, a chronic inflammatory disease, is pathologically associated with mitochondrial dysfunction. Mitochondria contribute to oxidative stress, vascular endothelial dysfunction, and chronic inflammatory cascades through pathways such as dynamic imbalance, abnormal epigenetic regulation, disruption of multi-organelle communication, and dysregulation of cell death signaling. Targeting mitochondria has therefore emerged as a promising therapeutic strategy beyond conventional treatments , which often fail to address this underlying pathology. Recent advances in nanomaterials enable precise mitochondrial intervention. Although conventional therapies such as statins and anti-inflammatory drugs can partially mitigate symptoms, they do not directly correct mitochondrial abnormalities and are often limited by systemic side effects. Recent progress in nanotechnology has enabled the development of mitochondria-targeted delivery systems, including liposomes, polymeric nanoparticles, and biomimetic carriers. These platforms enhance mitochondrial accumulation by incorporating targeting motifs or exploiting the negative mitochondrial membrane potential and specific interactions with outer membrane proteins. Among these, TPP⁺-modified liposomes can target the mitochondrial matrix via electrostatic interactions, effectively delivering drugs such as coenzyme Q10 to mitochondria, offering notable clinical potential. Moreover, Szeto-Schiller 31, which targets mitochondrial electron transport chain repair and reduces the secretion of inflammatory cytokines, has entered Phase II clinical trials. This review discusses the mechanistic role of mitochondrial dysfunction in atherosclerosis and evaluates the application of mitochondria-targeted delivery systems in atherosclerosis therapy. It also highlights the challenges these systems face, including issues related to delivery efficiency, biosafety, and targeting specificity. By linking molecular mechanisms with translational innovation, it highlights the significant potential of mitochondrial-targeted therapies.