Oropharyngeal squamous-cell carcinoma (OPSCC) poses significant challenges in diagnosis, treatment, and management and has important medico-legal and forensic implications. In particular, the management of OPSCC and its treatment-related complications can often be challenging. In cases with advanced OPSCC, a loco-regional extension of the tumor can contribute to the destruction of oral cavity tissues, while the radiotherapy treatment can induce profound changes in tissue morphology and structure. These changes, which resemble tumor neoplasms and endovascular effects, are related to a higher risk of fatal bleeding, as reported in the case study illustrated, in which a hemorrhage occurred from a lingual artery, originating from an ulcerative, necrotic, hemorrhagic lesion on the tongue. Bleeding complications in OPSCC and prolonged radiotherapy are associated with high mortality and require comprehensive management strategies to improve survival and quality of life. Autopsy investigations, contributing to the definition of post-mortem diagnosis, can provide valuable insights into the pathogenetic mechanisms underlying bleeding and guide therapeutic decisions and preventive measures. The integration of autopsy and histopathological investigation into clinical practice should be considered as a necessary support to optimize the management of complications in advanced OPSCC patients, emphasizing the importance of a patient-centered approach and continued research.