<p>The treatment of head and neck squamous cell carcinoma (HNSCC) remains a significant hurdle in clinical oncology, primarily due to the tumor’s intricate and immune-suppressing environment, its diverse genetic and observable characteristics, and its tendency to spread locally and to distant sites, further complicated by the development of drug insensitivity. Standard treatment approaches frequently fall short in effectively managing these complex features. This article provides a critical assessment of the developing area of sophisticated drug delivery methods (DDSs) aimed at improving treatment results in HNSCC. The specific attributes of the HNSCC tumor environment are examined, with a focus on the disrupted structure of the extracellular matrix (ECM), its involvement in the spread of tumor cells through the bloodstream and the establishment of metastatic tumors, and the various ways in which drug resistance arises. Additionally, we assess how novel DDS technologies might overcome these challenges through directed delivery to particular tumor microenvironment targets, precise control of cancer-driving signaling pathways, and the avoidance of drug resistance mechanisms. This overview summarizes recent progress in DDS technologies customized for HNSCC treatment, with a particular emphasis on therapies using nanoparticles and immune-based drug delivery, highlighting their potential to address the many difficulties associated with this difficult-to-treat cancer. We will explore the progression of these treatment strategies from laboratory research to clinical practice and the ongoing efforts to improve patient survival.</p> Graphical abstract <p></p>