Background: Head and neck squamous cell carcinomas (HNSCC) are aggressive malignancies with high mortality and poor prognosis. Pseudogenes with altered expression during HNSCC progression may serve as potential biomarkers for early detection, prognosis, and therapy selection. Methods: In this report, we analyzed the expression of ANXA2P2 and PA2G4P4 pseudogenes in HNSCC patients using data from The Cancer Genome Atlas. Clinical correlations were assessed through UALCAN and cBioPortal. Functional enrichment was investigated using REACTOME, ESTIMATE, and Gene Set Enrichment Analysis. Statistical analyses were performed with GraphPad Prism 8. Results: Both ANXA2P2 and PA2G4P4 were significantly upregulated in HNSCC compared to normal tissue. Their expression varied based on HPV status and was negatively correlated with overall survival. High pseudogene expression was associated with dysregulated oncogenic pathways, while low expression was linked to distinct immunological profiles. Conclusions: ANXA2P2 and PA2G4P4 exhibit oncogenic properties in HNSCC and hold potential as diagnostic and prognostic biomarkers.