<p>Head and neck squamous cell carcinoma (HNSCC) is a complex, aggressive and heterogeneous malignancy with trends rising rapidly worldwide. Tobacco use, alcohol consumption and human papillomavirus (HPV) infection are the leading risk factors associated with the occurrence of HNSCC. Standard treatments, including radiotherapy, chemotherapy, and surgical resection, are often associated with severe side effects and limited success, particularly in advanced, recurrent, or metastatic disease. Though the introduction of immune checkpoint inhibitors has reshaped the management of recurrent or metastatic disease, the clinical impact remains limited as a majority of patients do not achieve expected prognosis, attributed to a “cold” tumor microenvironment. Therefore, to enhance the clinical outcomes of HNSCC patients, it is priority to investigate more effective and well-tolerated targeted medicines. This review provides insights about the current treatment strategies, challenges associated with these traditional approaches along with shedding light on the state-of-the-art HNSCC treatment modalities such as advanced surgery, immunotherapy, epigenetics and cancer stem cell targeting, etc. Moreover, therapies involving varied sophisticated combinations of the abovementioned conventional approaches and these advanced treatment modalities have yielded better HNSCC prognosis in multiple preclinical and clinical settings. Continued multidisciplinary research targeting molecular pathways and innovative drug delivery systems hold the potential to remarkably enhance treatment efficacy while preserving patient’s quality of life.</p> Graphical abstract <p></p>