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Atherosclerosis (AS), the pathological basis of cardiovascular diseases, remains a leading global cause of mortality. Its pathogenesis involves chronic inflammation, impaired clearance of apoptotic cells (efferocytosis), and lipid dysregulation within the arterial wall. The CD47-SIRPα signaling axis, a key immune checkpoint, has been identified as a critical regulator integrating these processes in the atherosclerotic plaque microenvironment. This review systematically details the multifaceted role of the aberrantly activated CD47-SIRPα axis in driving AS progression. We elaborate on its molecular architecture and how it pathologically inhibits macrophage efferocytosis by disrupting cytoskeletal dynamics and integrin-mediated adhesion. The axis concurrently sustains a pro-inflammatory state within plaques and disrupts cholesterol homeostasis by promoting lipid influx and inhibiting efflux, thereby accelerating foam cell formation. We further evaluate emerging therapeutic strategies targeting this axis, including monoclonal antibodies, engineered SIRPα-Fc fusion proteins, and multifunctional nanocarriers designed for plaque-targeted delivery. These approaches aim to restore efferocytosis, mitigate inflammation, and resolve lipid accumulation. While preclinical results are encouraging, challenges such as cell-type-specific effects, potential on-target hematological toxicity, and the need for precise delivery persist. Therapeutic modulation of the CD47-SIRPα axis presents a promising immunometabolic strategy for AS. Future directions should focus on developing cell- or context-selective modulators to enhance safety, identifying biomarkers for patient stratification, and rationally combining these novel agents with established lipid-lowering and anti-inflammatory therapies to address the residual risk in atherosclerotic cardiovascular disease.