Objective To establish a double-knockout mouse model of apolipoprotein E ( ApoE) and macrophage-specific Krüppel-like factor 2 (KLF2) and to investigate the role of macrophage KLF2 in the progression of atherosclerosis. Methods KLF2^{flox / flox}/ Lyz2-Cre⁺ mice were crossed with ApoE^{- / -} mice over multiple generations to generate KLF2^{flox / flox}/ Lyz2-Cre⁺/ ApoE^{- / -} mice. KLF2 knockout efficiency at the mRNA and protein levels was verified by reverse transcription quantitative polymerase chain reaction(RT-qPCR) and Western Blot analysis. Atherosclerosis was induced by feeding mice a high-fat diet. Plaque formation and lipid metabolism were compared between the model group (KLF2^{flox / flox}/ Lyz2-Cre⁺/ ApoE^{- / -}) and the control group ( KLF2^{flox / flox}/ ApoE^{- / -}). Results A macrophagespecific KLF2 and ApoE double-knockout mouse model ( KLF2^{flox / flox}/ Lyz2-Cre⁺/ ApoE^{- / -}) was successfully established. Histopathological analysis demonstrated significantly increased aortic root plaque area and lipid accumulation in the model group compared with controls. In addition, the model group exhibited markedly elevated serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels, as well as increased hepatic lipid accumulation.Macrophage infiltration within aortic plaques was also significantly higher in the model group. Conclusions Macrophagespecific deletion of KLF2 accelerates atherosclerotic plaque progression, potentially through dysregulation of lipid metabolism and enhanced macrophage adhesion and migration. This model provides a valuable experimental platform for further elucidating the role of macrophage KLF2 in atherosclerosis and related cardiovascular diseases.