Atherosclerosis is a chronic arterial disease and the leading cause of stroke and myocardial infarction. Micro-RNAs (miRNAs or miRs) have been reported to act as essential modulators during the progression of atherosclerosis. Although miR-let-7g has been demonstrated to contribute to maintaining endothelial function and vascular homeostasis, it is not known whether miR-let-7g exerts a therapeutic effect on experimental atherosclerosis. The aim of this study was to investigate the effects of miR-let-7g on atherosclerosis in vivo and in vitro and to explore its underlying mechanisms. Data from our study showed that exogenous lectin‑like oxidized low‑density lipoprotein receptor‑1 (LOX-1 or OLR1) overexpression resulted in the significant promotion of proliferation and migration of human aortic smooth muscle cells (ASMCs), whereas such changes induced by LOX-1 were obviously suppressed by transfection of miR‑let‑7g. We later confirmed that LOX-1 is a potential target of miR-let-7g, and miR-let-7g markedly inhibited LOX-1 expression in ASMCs by directly binding to the 3' untranslated region of LOX-1. Furthermore, in a hyperlipidemic apolipoprotein E knockout (ApoE-/-) mouse model, intravenous delivery of miR-let-7g mimics obviously attenuated high-fat diet-induced neointima formation and atherosclerotic lesions, accompanied by the significant downregulation of LOX-1, which was consistent with the effect of miR-let-7g on ASMCs. Taken together, our data revealed that miR-let-7g exhibits anti-atherosclerotic activity, at least partially by targeting the LOX-1 signaling pathway. This study suggests that miR-let-7g may be a therapeutic candidate for treating atherosclerosis, and provides novel insight into miRNA-based therapy for this disease.