Although many efforts have been made to investigate a promising biomarker for the diagnosis of papillary thyroid cancer (PTC), the currently available biomarkers lack the sensitivity to accurately characterize PTC. Here, we established a high-sensitivityt cell-free DNA (cfDNA) detection system using polydopamine-silica (PDA/SiO2) hybrids to enable clinically reliable analysis of PTC. The PDA/SiO2-coated beads improved the detection of DNA by 1.76-fold (p=0.031) compared to the conventional silica-based cfDNA capture system. The PDA-SiO2-coated beads were then applied for the detection of cfDNA from serum samples obtained from 37 PTC patients, and the BRAFV600E mutation status in captured DNA was analyzed using both quantitative polymerase chain reaction (qPCR) and digital droplet PCR (ddPCR). The BRAFV600E mutation status analyzed using both assays demonstrated a strong correlation with the multifocality of PTC, exhibiting area under receiver operating characteristic curve (AUC-ROC) of >0.964 (p<0.001). In contrast, none of the serum antigens or antibodies related to PTC or thyroid functions exhibited clinically significant prediction for detecting PTC patients with multifocal tumors. These findings suggest that cfDNA capture using PDA/ SiO2-coated beads is a promising approach for analyzing the BRAF mutation, which can serve as an excellent diagnostic biomarker for PTC.