Studies have demonstrated the essential functions of microRNAs (miRNAs) in cardiovascular disease. Herein, we explored the roles of miR-126 and miR-223 in the prediction of plaque stability in carotid atherosclerosis (CA).Patients with CA (N = 52) and healthy volunteers (N = 25) were recruited as the study subjects and controls. First, a miRNA microarray was performed to analyze the differentially expressed miRNAs in the serum of normal controls and patients with CA. Next, the correlations of miR-223 and miR-126 expression with plaque stability-related factors were analyzed. Then, the predictive efficacy of miR-223 and miR-126 on plaque stability was analyzed by the ROC curve, and the targeting relationships of miR-223 and miR-126 with COX2 were verified. Finally, the relationship between COX2 expression and CA plaque stability was analyzed. miR-223 and miR-126 were decreased in the serum of CA patients and had good diagnostic efficacy for CA. miR-223 and miR-126 in the serum of CA patients with unstable plaques were lower than that in patients with stable plaques. miR-223 and miR-126 were negatively correlated with plaque instability-related indicators, while COX2, a direct target of miR-223 and miR-126, was positively related to plaque instability-related indicators. Lowly expressed miR-223 and miR-126 in the serum of CA patients can be used as indicators for plaque stability.