The 5-year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) remains <50% due to risk of the recurrence and metastasis. Hypoxia patterns are a hallmark of HNSCC that are associated with its occurrence and progression. However, the precise role of hypoxia during HNSCC, such as the relationship between hypoxia, tumor immune landscape and cell communication orchestration remains largely unknown. The current study integrated data from bulk and single-cell RNA sequencing analyses to define the relationship between hypoxia and HNSCC. First, a scoring system named the hypoxia score (HS) was constructed based on hypoxia-related genes (HRGs) expression. The survival outcomes, stromal/immune/Estimate scores, responses to targeted inhibitors, and chemotherapeutic, and immunotherapy responses were distinct between a high HS group and a low HS group. Single-cell datasets showed different distributions of HS in immune cell populations. Furthermore, HLA-DPA1/CD4 axis was identified as a unique interaction between CD4+ T Conv and pDC cells. These findings may enhance the understanding of hypoxia characteristics associated with HNSCC.