Atherosclerosis, a chronic lipid-driven vascular inflammatory disease involving multiple cell types, is the primary cause of cardiovascular disease-related morbidity and mortality. Allograft inflammatory factor 1 (AIF-1) contributes to atherosclerosis development by affecting vascular smooth muscle cells (VSMCs). Increasing research indicates that VSMCs are pivotal in atherosclerosis progression, particularly in macrophage-like phenotypic switching, though the mechanism of AIF-1 VSMCs phenotypic switching is not well understood. This study aims to correlate AIF-1 expression with atherosclerosis development and VSMCs phenotypic switching. AIF-1 was expressed in the atherosclerotic plaques of patients with carotid artery narrowing and atherosclerosis mice. AIF-1 was expressed in ox-LDL treated VSMCs and promoted the apoptosis of VSMCs. AIF-1 significantly influenced macrophage-like VSMC numbers through the AIF-1/NF-κB pathway, enhancing lipid uptake and TNF-α and IL-6 secretion. This study showed increased AIF-1 expression in atherosclerotic plaques in both patients with carotid stenosis and an atherosclerosis animal model. AIF-1 facilitated VSMC dedifferentiation into macrophage-like cells, enhancing lipid uptake and inflammatory factor release through the AIF-1/NF-κB pathway.