Compelling evidence has demonstrated that the M1 macrophage phenotype is central to atherosclerotic lesion development. SIRT2, an NAD⁺-dependent sirtuin deacetylase, is involved in modulating macrophage polarization. However, the role of SIRT2 in atherosclerotic progression remains unknown. Female LDL receptor knockout (LDLr^-/-) mice were randomly divided into four groups for treatment with saline, empty lentivirus, lentivirus-SIRT2, or shRNA-SIRT2 for 4 weeks. Thereafter, the mice were fed an atherogenic high-fat diet (HFD) for another 8 weeks. Atherosclerotic plaques were assessed in the aortic sinus by morphometry, immunohistochemistry and immunofluorescence analyses. Aortic levels of macrophage polarization markers were analysed by Western blot and immunofluorescence analyses. We found that lentivirus-SIRT2-treated LDLr^-/- mice had decreased plaque areas in the aortic sinus and developed a more stable plaque phenotype, as shown by decreased macrophage infiltration and apoptosis. In addition, treatment with lentivirus-SIRT2 significantly reduced the expression of iNOS (inducible nitric oxide synthase) and increased the levels of ARG-1 (arginase-1) in atheromas. These findings suggest that SIRT2 inhibited atherosclerotic plaque progression and enhanced plaque stability in LDLr^-/- mice by inhibiting macrophage polarization towards the M1 phenotype.