Atherosclerotic cardiovascular diseases (ASCVDs) remain the primary cause of morbidity and mortality. Macrophages are involved in the progression and regression of atherosclerosis, and macrophage amino acid metabolism is important during this process. Here, we identified that the expression of cellular serine importer SFXN1 was upregulated by oxidized low-density lipoprotein and specifically enhanced in the macrophages of atherosclerotic plaques. Macrophage-specific SFXN1 knockout in ApoE-null mice attenuated atherosclerotic lesions and increased the plaque stability under a 16-week Western diet. ApoE-/-SFXN1-KO displayed unchanged blood lipids, decreased inflammatory cytokines, and increased antioxidant capacity. Mechanistically, SFXN1-mediated serine uptake and synthesis inhibited classical activated macrophage (M1) polarization via reducing Stat1 phosphorylation and promoted alternatively activated macrophage (M2) polarization by enhancing Stat6 phosphorylation. Macrophage-targeting lipid nanoparticles loaded with serine modulated macrophage polarization and ameliorated the procession of atherosclerosis. These findings reveal the critical role of SFXN1 in phenotypic switching in the macrophages and indicate that SFXN1-mediated amino acid metabolism could be utilized as a novel therapeutic strategy in the prevention of ASCVDs.