The prognosis of patients with advanced arteriosclerosis is bleak due to the lack of understanding of arteriosclerosis. Epigenetics-based DNA methylation plays an important role in the pathogenesis of arteriosclerosis. Hence, we aimed to identify the epigenetics-related aberrantly methylated differentially expressed genes (AMDEGs) in arteriosclerosis. A gene expression dataset and DNA methylation dataset were downloaded from the Gene Expression Omnibus database, and AMDEGs were identified on the basis of the relationship between methylation and expression. Subsequently, the expression levels of candidate hub genes were detected in human peripheral blood mononuclear cells (PBMCs) from atherosclerotic patients and control subjects by RT-qPCR and Western blot. Lastly, the methylation level of the target gene was detected using the MassARRAY method. In the present study, the hypermethylated and downregulated genes were mainly involved in vascular smooth muscle contraction. The hypomethylated and upregulated genes were markedly associated with immune-inflammatory processes. Following validation, LMOD1 was identified as the target gene, which was hypermethylated and downregulated in arteriosclerosis. The methylation levels of CpG sites in LMOD1 promoter were detected to be elevated in the PBMCs of atherosclerotic patients. In conclusion, AMDEGs identified in the present study may assist in understanding the pathogenesis of arteriosclerosis. LMOD1 exhibits potential as a promising diagnostic and therapeutic biomarker for arteriosclerosis.