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Hypoxia-inducible factor 1-alpha (HIF1A) is a key transcription factor aiding tumor cells’ adaptation to hypoxia, regulated by the prolyl hydroxylase family (EGLN1-3) by directing toward degradation pathways. DNA methylation potentially influences EGLN and HIF1A levels, impacting cellular responses to hypoxia. We examined 96 HNSCC patients and three cell lines, analyzing gene expression of <i>EGLN1-3</i>, <i>HIF1A</i>, <i>CA9</i>, <i>VEGF</i>, and <i>GLUT1</i> at the mRNA level and EGLN1 protein levels. Methylation levels of <i>EGLNs</i> and <i>HIF1A</i> were assessed through high-resolution melting analysis. Bioinformatics tools were employed to characterize associations between <i>EGLN1-3</i> and <i>HIF1A</i> expression and methylation. We found significantly higher mRNA levels of <i>EGLN3</i>, <i>HIF1A</i>, <i>GLUT1</i>, <i>VEGF</i>, and <i>CA9</i> (<i>p</i> = 0.021; <i>p</i> < 0.0001; <i>p</i> < 0.0001; <i>p</i> = 0.004, and <i>p</i> < 0.0001, respectively) genes in tumor tissues compared to normal ones and downregulation of the <i>EGLN1</i> mRNA level in tumor tissues (<i>p</i> = 0.0013). In HNSCC patients with hypermethylation of <i>HIF1A</i> in normal tissue, we noted a reduction in <i>HIF1A</i> mRNA levels compared to tumor tissue (<i>p</i> = 0.04). In conclusion, the differential expression of <i>EGLN</i> and <i>HIF1A</i> genes in HNSCC tumors compared to normal tissues influences patients’ overall survival, highlighting their role in tumor development. Moreover, DNA methylation could be responsible for <i>HIF1A</i> suppression in the normal tissues of HNSCC patients.