<p>Atherosclerosis is the main cause of coronary artery disease (CAD), and it is not easy to be detected at the early stage. To mine biomarkers for early diagnosis of CAD. Potential molecular mechanism was mined using the biological databases. The qPCR and western blotting were used to detect the expression of LINC01220, hsa-miR- 6727 - 5p, and FBLN5. Dual-luciferase report assay and overexpression experiment were used to explore the regulation among LINC01220, hsa-miR- 6727 - 5p, and FBLN5. The cell viability, migration, apoptosis, and senescence were evaluated by CCK- 8, transwell, Annexin V/PI staining, and detection of aging markers. The differentiation of human bone marrow monocytes (HBMMs) was evaluated by detecting the expression of CD68, CD86, and iNOS. The clinical analysis was performed based on the blood samples from healthy individuals and asymptomatic CAD patients. The receiver operating characteristic (ROC) curve and logistic regression analysis were used to evaluate the diagnostic value of LINC01220/hsa-miR- 6727 - 5p/FBLN5 in CAD. Overexpression of LINC01220 promoted FBLN5 expression by down-regulating hsa-miR- 6727 - 5p. LINC01220 rescued human aortic endothelial cell (HAEC) viability injury, apoptosis, and senescence induced by oxidized low-density lipoprotein (ox-LDL), and inhibited HBMM migration and differentiation, by regulating hsa-miR- 6727 - 5p/FBLN5. The area under curve (AUC) of the LINC01220/hsa-miR- 6727 - 5p/FBLN5 axis in diagnosing CAD was 0.954 (0.919–0.990), with sensitivity of 91.9% and specificity of 91.7%. LINC01220 may hinder CAD progression by negatively regulating hsa-miR- 6727 - 5p which targeted FBLN5, and they were potential biomarkers of CAD.</p>