To propose and verify a hypothesis that miR-17-5p knockdown may mitigate atherosclerotic lesions using atherosclerotic ApoE(-/-) mice as serum microRNA-17-5p (miR-17-5p) is elevated in patients with atherosclerosis. The level of miR-17-5p was higher while the level of very low density lipoprotein receptor (VLDLR), a predicted target of miR-17-5p, was lower in the peripheral blood lymphocytes (PBLs) of atherosclerosis patients as compared with control PBLs. ApoE(-/-) mice fed with a high-cholesterol diet displayed marked atherosclerotic vascular lesions, which were ameliorated after treatment with antagomiR-17-5p. Moreover, the decreased VLDLR in atherosclerotic mice was partly restored when miR-17-5p was antagonized. Further, luciferase assay confirmed VLDLR as a direct target of miR-17-5p in vascular smooth muscle cells (VSMCs). In addition, the elevated expression of proprotein convertase subtilisin kexin 9 (PCSK9), a secreted protease that binds to and promotes VLDLR degradation, in the atherosclerotic mice was suppressed by antagomiR-17-5p. A novel interaction between miR-17-5p and VLDLR is revealed and suggests that miR-17-5p may be a potential therapeutic target for AS.