Head and neck cancer (HNC) is the sixth cause of cancer-related death worldwide. Head and neck squamous cells carcinoma (HNSCC) is the most frequent subtype of HNC. The development of HNSCC is associated to alcohol consumption, smoking or infection by high-risk human Papillomavirus (HR-HPV). Although the incidence of cancers associated with alcohol and tobacco has diminished, HNSCC associated with HR-HPV has significantly increased in recent years. However, HPV-positive HNSCC responds well to treatment, which includes surgery followed by radiation or chemoradiation therapy. Radiation therapy (RT) is based on ionizing radiation (IR) changing cell physiology. IR can directly interact with deoxyribonucleic acid (DNA) or produce reactive oxygen and nitrogen species (RONS), provoking DNA damage. When DNA damage is not repaired, programmed cell death (apoptosis and/or autophagy) is induced. However, cancer cells can acquire resistance to IR avoiding cell death, where reprogramming of energy metabolism has a critical role and is intimately connected with hypoxia, mitochondrial physiology, oxidative stress (OS) and autophagy. This review is focused on the reprogramming of energy metabolism in response to RT in HPV-positive and HPV-negative HNSCC, showing their differences in cellular metabolism management and the probable direction of treatments for each subtype of HNSCC.