Despite growing interest in chloride intracellular channels (CLICs) research, their collective role in head and neck squamous cell carcinoma (HNSCC) remains unexplored. The study aims to comprehensively characterise the role of CLICs in HNSCC through integrative bioinformatic analyses. Material and methods: We performed an integrative bioinformatic analysis of TCGA-HNSC and CPTAC datasets, complemented by ESTIMATE, TISIDB, and gene set enrichment analysis (Hallmark, C6, C7), to characterise expression, promoter methylation, prognostic significance, immune interactions, and biological functions of CLIC1–CLIC6 in HNSCC. Results: Chloride intracellular channels 4 was overexpressed in tumours, whereas CLIC3, CLIC5, and CLIC6 were down-regulated at mRNA and protein levels. Promoter methylation patterns were concordant with expression changes, with hypermethylation of CLIC1 and CLIC6, and hypomethylation of CLIC3, CLIC4, and CLIC5. Expression differed significantly across molecular subtypes and anatomic sites, with tumours of the oral cavity showing the most distinct profile. We report, for the first time, the differential expression of CLIC2, CLIC3, CLIC4, and CLIC6 between human papillomavirus (HPV)-positive and HPV-negative oropharyngeal cancers. Although CLICs expression did not stratify overall survival, CLIC2, CLIC5, and CLIC6 correlated with ESTIMATE-derived immune and stromal scores, and CLIC5 showed strong associations with multiple lymphoid and myeloid subsets. Gene set enrichment analysis revealed enrichment of epithelial-mesenchymal transition, E2F targets, and KRAS-up signatures, with notable antagonism between CLIC1–CLIC4 (oncogenic pathways) and CLIC1–CLIC6 (immune signatures). Conclusions: Chloride intracellular channels family members exhibit distinct transcriptional, epigenetic, immune, and functional profiles in HNSCC, highlighting their potential diagnostic and mechanistic relevance. These findings establish a foundational framework for future translational and mechanistic studies of CLICs in head and neck cancer.