Of the HNSCC patients analyzed, 54.1% showed methylation in the promoter of at least one of the studied genes (i.e., DAPK, DCC, MINT-31, TIMP3, p16, MGMT, and CCNA1) in saliva ctDNA, with a significantly lower local disease control and overall survival in patients with recurrence. In addition, among all sites analyzed, a higher percentage of patients with OSCC, with respect to the other sites, showed DNA hypermethylation. Detection of DNA hypermethylation in saliva ctDNA can potentially predict local recurrence and overall survival in OSCC patients. Here, DAPK1 is linked to head and neck squamous cell carcinoma.