Head and neck squamous cell carcinoma (HNSCC) is a major global health burden, often associated with poor prognosis and limited therapeutic options. Long non-coding RNAs (lncRNAs), a diverse group of non-coding RNA molecules > 200 nucleotides in length, have emerged as critical regulators in the pathogenesis of HNSCC. This review summarizes the mechanisms through which certain lncRNAs regulate chromatin modification, mRNA splicing, and interactions with RNA-binding proteins and contribute to the development and progression of HNSCC. Interaction of lncRNAs with key oncogenic pathways, such as PI3K/AKT and Wnt/β-catenin, highlights their importance in tumor progression. The role of lncRNAs, such as ELDR, MALAT1, NEAT1, HOTAIR, and UCA1, which promote cell proliferation, metastasis, immune evasion, and therapy resistance is discussed. Moreover, several lncRNAs are being evaluated in clinical trials for their potential as biomarkers, reflecting their clinical significance. We further address the challenges and opportunities for targeting lncRNA therapeutically, highlighting the promise of lncRNA-based interventions for personalized cancer treatment. Gaining insight into the function of lncRNAs in HNSCC could pave the way for novel therapeutic strategies to potentially improve patient outcomes.