This systematic review aims to provide a comprehensive understanding of the role of human papillomavirus (HPV) in head and neck cancer of unknown primary (HNCUP). HNCUP is a rare type of cancer with an unknown primary site, which makes it difficult to diagnose and treat. The review includes articles published between 2013 and 2023 that investigated the prevalence of HPV in HNCUP, its association with clinical outcomes, and its potential implications for diagnosis and treatment. The search was conducted in 11 electronic databases, and the gray literature: Cochrane, Cumed, IBECS, JAMA Network, LILACS, MEDLINE Ovid, MEDLINE-EBSCO, PubMed, Scopus, SciELO, and Taylor & Francis Online; a total of 23 studies met the inclusion criteria. The review found that HPV is present in a significant proportion of HNCUP cases, ranging from 15.5% to 100%. HNCUP incidence is increasing, and the presence of HPV was associated with improved clinical outcomes in some studies, such as overall survival and disease-free survival; but was found to have no association with outcomes in others. This may have implications for diagnostic and treatment strategies. The findings of this review suggest that further research is needed to better understand the role of HPV in HNCUP and to develop targeted therapies for this disease.