Atherosclerosis (AS) is a chronic progressive inflammatory disease and a leading cause of death worldwide. Being a novel adipokine, chemerin is reported to be positively correlated with the severity of AS, yet its underlying mechanisms in AS remains elusive. It is well-known that AS development is significantly attributed to abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, we investigated the role of the chemerin / chemokine-like receptor 1 (CMKLR1, chemerin receptor) signaling, and the potential therapeutic effect of curcumin in VSMCs proliferation and migration during AS by establishing a high fat diet (HFD) mouse model. We found that CMKLR1 was highly expressed in HFD-induced AS tissues and that its expression level was positively correlated with aortic proliferation. Knockdown of CMKLR1 significantly inhibited VSMCs proliferation and migration, as evidenced by the EdU-incorporation assay, wound healing assay, and the induction of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-9 (MMP-9) expression. Furthermore, we discovered that Lipocalin-2 (LCN2) acts as a key factor involved in CMKLR1-mediated VSMCs proliferation and migration via the p38 / MAPK and Wnt / β-catenin signaling pathways, and we demonstrated that curcumin inhibits VSMCs proliferation and migration by inhibiting chemerin / CMKLR1 / LCN2, thereby reducing AS progression. Our findings suggest that chemerin / CMKLR1 activation promotes the development of AS; hence, targeting the chemerin / CMKLR1 / LCN2 signaling pathway may be a reasonable treatment modality for AS.