Simple SummaryA subgroup of cancers that arises in the zone of the head and neck (HNCs) are caused by some types of human papillomavirus (HPV), so called high-risk (HR)-HPVs. HR-HPVs promote signaling pathways alterations involved in the initiation and progression of cancer. Among them, phosphatidyl inositol 3-kinase (PI3K)/AKT/mTOR signaling is involved in increasing cell proliferation, migration, and invasion. In this review, we dissect the role of PI3K/AKT/mTOR in HR-HPV-associated HNCs development and the impact as a potential therapeutic target.AbstractHigh-risk human papillomaviruses (HR-HPVs) are the causal agents of cervical, anogenital and a subset of head and neck carcinomas (HNCs). Indeed, oropharyngeal cancers are a type of HNC highly associated with HR-HPV infections and constitute a specific clinical entity. The oncogenic mechanism of HR-HPV involves E6/E7 oncoprotein overexpression for promoting cell immortalization and transformation, through the downregulation of p53 and pRB tumor suppressor proteins, among other cellular targets. Additionally, E6/E7 proteins are involved in promoting PI3K/AKT/mTOR signaling pathway alterations. In this review, we address the relationship between HR-HPV and PI3K/AKT/mTOR signaling pathway activation in HNC with an emphasis on its therapeutic importance.