Coronary artery disease (CAD) is one of the most common heart diseases, characterized by the hardening and narrowing of arteries, resisting blood supply to cardiac muscle. Despite extensive research, the pathogenesis and therapeutic options for CAD remain limited. Epigenetic regulation plays a critical role in CAD progression. Here, we report a unique DNA methylation-miRNA-mRNA regulatory network for CAD, delineated through DNA methylation assays, miRNA and mRNA sequencing, bioinformatics analyses. We also identified key signaling pathways in this network, including the miR194 promoter-miR194-MAPK signaling pathway by pyrosequencing, methylation PCR, qRT-PCR. This pathway could play a role in CAD by apoptosis. Our findings suggested that this signaling pathway may be a potential therapeutic target for CAD. We believe that our study significantly contributes to an improved understanding of the role of specific miRNAs methylation, miRNA, and mRNAs in CAD pathogenesis.