Herpes simplex virus (HSV) infection can potentially mask underlying malignancies, complicating clinical diagnosis and potentially delaying the detection of a serious pathology. The present study describes the case of a 37-year-old man with a 20-year smoking history that presented with a tongue ulcer masked by HSV infection, who underwent comprehensive diagnostic investigations. Initial histopathological examination revealed characteristic HSV infection features, including multinucleation and intercellular bridge destruction. Despite symptomatic improvement of the viral infection, persistent leukoplakia and erythroplakia warranted further investigation. Sequential biopsies and clinical monitoring led to a partial glossectomy. Final pathology confirmed squamous cell carcinoma of the tongue with negative tumor margins. The present case emphasizes the critical importance of thorough evaluation of persistent oral lesions, especially in high-risk patients, as viral infections can complicate the diagnosis of underlying malignancies. Furthermore, it highlights the need for continued surveillance when clinical suspicion remains high, even after initial benign findings.