Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of plaque within the arteries. Despite advances in therapeutic strategies including anti-inflammatory, antioxidant, and lipid metabolism modulation treatments over the past two decades, the treatment of atherosclerosis remains challenging, as arterial damage is the result of interconnected pathological factors. Therefore, current monotherapies often fail to address the complex nature of this disease, leading to insufficient therapeutic outcomes. This review addressed this paucity of effective treatment options by comprehensively exploring the potential for combination therapies and advanced drug co-delivery systems for the treatment of atherosclerosis. We investigated the pathological features of and risk factors for atherosclerosis, underscoring the importance of drug combination therapies for the treatment of atherosclerotic diseases. We discuss herein mathematical models for quantifying the efficacy of the combination therapies and provide a systematic summary of drug combinations for the treatment of atherosclerosis. We also provide a detailed review of the latest advances in nanoparticle-based drug co-delivery systems for the treatment of atherosclerosis, focusing on the design of carriers with high biocompatibility and efficacy. By exploring the possibilities and challenges inherent to this approach, we aim to highlight cutting-edge technologies that can foster the development of innovative strategies, optimize drug co-administration, improve treatment outcomes, and reduce the burden of atherosclerosis-related morbidity and mortality on the healthcare system.