Liquid biopsy analysis of cell-free DNA (cfDNA) has revolutionized cancer research by enabling non-invasive assessment of tumor-derived genetic and epigenetic changes. In this study, we conducted a comprehensive paired-sample differential methylation analysis (psDMR) on reprocessed methylation data from two large datasets, CPTAC and TCGA, to identify and validate differentially methylated regions (DMRs) as potential cfDNA biomarkers for head and neck squamous cell carcinoma (HNSC). Our hypothesis is that the paired sample test provides a more suitable and powerful approach for the analysis of heterogeneous cancers like HNSC. The psDMR analysis revealed a significant number of overlapped hypermethylated DMRs between two datasets, indicating the reliability and relevance of these regions for cfDNA methylation biomarker discovery. We identified several candidate genes, including CALCA, ALX4, and HOXD9, which have been previously established as liquid biopsy methylation biomarkers in various cancer types. Furthermore, we demonstrated the efficacy of targeted region analysis using cfDNA methylation data from oral cavity squamous cell carcinoma and nasopharyngeal carcinoma patients, further validating the utility of psDMR analysis in prioritizing cfDNA methylation biomarkers. Overall, our study contributes to the development of cfDNA-based approaches for early cancer detection and monitoring, expanding our understanding of the epigenetic landscape of HNSC, and providing valuable insights for liquid biopsy biomarker discovery not only in HNSC and other cancer types.