Macrophages’ function play a vital role in the progression of atherosclerosis (AS), and miRNAs can modulate inflammatory cytokine secretion, lipid uptake and apoptosis of macrophages. miR-152 is down-regulated in the serum samples of AS patients and inhibits the migration of human umbilical vein endothelial cell, suggesting that miR-152 exerts a role in the atherogenesis. Nevertheless, the function of miR-152 in the inflammatory reaction of macrophages remains unexplored. Besides, bioinformatics shows that KLF5 is a direct target of miR-152. As a result, the objective of this study is to investigate the effects and mechanism of miR-152/KLF5 in the inflammatory reaction of macrophages. ApoE knockdown mouse (ApoE^-/-) fed with high fat diet (HFD) was used as animal AS models. Ox-LDL treated RAW264.7 cell was used as cell model. Results showed that miR-152 expression was reduced, while KLF5 expression was elevated in the aortic tissues of AS mice, as compared with that of the control mice. Up-regulation of miR-152 significantly reduced the elevated expression of IL-1, IL-6 and TNF-α mediated by ox-LDL in the cultural supernatant of RAW264.7 cells and reduced β-catenin expression, whereas these effects were all neutralized when KLF5 was up-regulated in the base of miR-152 up-regulation. In conclusion, this study illustrates that miR-152 alleviates the pathogenesis of AS through inhibiting inflammatory responses by targeting KLF5, in which β-catenin might involves in. Our study provides a possibility of consideration of miR-152/KLF5 as a target for AS treatment.