© 2021, The Author(s), under exclusive licence to Springer Nature B.V.Background: Although patients with coronary artery disease (CAD) have a high mortality rate, the pathogenesis of CAD is still poorly understood. During the past decade, microRNAs (miRNAs) have emerged as new, potential diagnostic biomarkers in several diseases, including CAD. This study aimed to investigate the expression profiles of miRNAs in individuals with CAD and non-CAD. Methods and results: The Agilent’s microarray analyses were performed to compare the whole blood miRNA profile of selected individuals with severe CAD (n = 12, ≥ 90% stenosis) and non-CAD (n = 12, ≤ 20 stenosis). Expressions of selected differentially expressed miRNAs (DEMs) were analyzed for validation in individuals with critical CAD (n = 50) and non-CAD (n = 43) using real-time PCR. Target prediction tools were utilized to identify miRNA target genes. We identified 6 DEMs that were downregulated in CAD patients, which included hsa-miR-18a-3p and hsa-miR-130b-5p, that were analyzed for further testing. Expression levels of hsa-miR-130b-5p were found negatively correlated with SYNTAX score and stenosis in female CAD patients (p < 0.05). In addition, both miRNAs were found positively correlated with plasma HDL and inversely correlated with fasting triglyceride levels (p < 0.05). In linear regression analysis adjusted for several confounders, the correlations have remained statistically significant. Computational prediction of target genes indicated a relevant role of hsa-miR-130b-5p and hsa-miR-18a-3p in modulating the expression of genes associated with cardiovascular diseases. Conclusion: Our findings highlight a significantly different pattern of miRNA expression in CAD patients in microarray results. Hsa-miR-18a-3p and hsa-miR-130b-5p might serve as biomarkers of CAD development and progression and warrant further attention.