PURPOSE: Papillary thyroid carcinoma (PTC) is the most common malignant thyroid neoplasm, accounting for approximately 85% of all follicular cell-derived thyroid nodules. This study aimed to assess the diagnostic potential of circulating microRNA-146a-5p and microRNA-221-3p as biomarkers for PTC and their usefulness in monitoring disease progression during patient follow-up. METHODS: An observational study was conducted on two cohorts of PTC patients and healthy controls (HCs) using digital PCR. We collected patients' clinical, biochemical, and imaging data during the post-surgery surveillance. We analyzed the levels of circulating miRNAs in serum samples of patients before surgery and during the follow-up, including those with indeterminate/biochemical incomplete response (IndR/BIR) and residual thyroid tissues (Thy Residue). RESULTS: Both miR-146a-5p and miR-221-3p were confirmed as effective biomarkers for PTC diagnosis. They enabled differentiation between pre-surgery PTC patients and HCs with an area under the curve (AUC) of 92% and 87.3%, respectively, using a threshold level of 768,545 copies/uL for miR-146a-5p and 389,331 copies/uL for miR-221-3p. It was found that miRNA fold change levels, rather than absolute levels, can be useful during patient follow-up. In particular, we found that a fold change of 2 for miR-146a-5p and 2.2 for miR-221-3p can identify a progressive disease, regardless of the presence of TgAbs or remnant thyroid. CONCLUSION: MiRNA-146a-5p and miRNA-221-3p, particularly the former, could be valuable diagnostic biomarkers for PTCs. They also seem to be effective in monitoring disease progression during patient follow-up by evaluating their fold change, even when thyroglobulin is uninformative.