BACKGROUND Dickkopf Wnt signaling pathway inhibitor (DKK) gene family, which is known to inhibit the Wnt regulation process, is widely found in cancers. However, the roles and functions of specific family members in head and neck squamous cell carcinoma (HNSCC) are still unclear. MATERIAL AND METHODS Online bioinformatics tools (Oncomine, UALCAN, Kaplan-Meier plotter, GEPIA, Metascape, and STRING) were used to analyze the relationships between distinct DKKs and HNSCC. The transcriptome expression, clinical association, functions, pathways, and protein-protein interaction networks of DKKs in HNSCC were explored. RESULTS The mRNA expression of DKK1, DKK3, and Dickkopf-like acrosomal protein 1 (DKKL1) in HNSCC was significantly higher than in normal tissues, while that of DKK4 was lower. The mRNA expression of DKK1, DKK3, and DKKL1 was elevated in higher-grade HNSCC. The mRNA expression of DKK1 and DKK3 was elevated in human papillomavirus (HPV)-negative HNSCC, while DKKL1 had a higher mRNA expression in HPV-positive HNSCC. In addition, DKK1 was significantly associated with unfavorable overall survival in HNSCC patients. DKK3 was more likely to be a negative factor for the 5-year survival rate, while DKK4 was the opposite. DKK1 function was mainly enriched in GTPase-mediated signal transduction. Porcupine O-acyltransferase, a key regulator of the Wnt signaling pathway, was also associated with DKK1 in the protein-protein interaction network. CONCLUSIONS With regard to improving the therapeutic strategies of HNSCC in the future, DKK1 could be an unfavorable prognostic biomarker. DKK3, DKK4, and DKKL1 might be potential biomarkers for HNSCC.