Objective: In Mexico, head and neck cancers pose a significant health burden. GLOBOCAN reported approximately 3183 new cases and 1636 deaths in 2020. Despite being the sixth leading cause of cancer incidence and mortality worldwide, data on epidemiology and treatment patterns in Mexico remain limited. This study aimed to characterize the profile, clinical features, and management of patients with Stage III–IVB head and neck squamous cell carcinoma (HNSCC) in a real-world setting. Methods: We retrospectively analyzed a database of 187 patients with Stage III, IVA, or IVB HNSCC treated at the University Hospital Dr. José Eleuterio González. Demographics, disease characteristics, and treatment patterns were summarized as frequencies and percentages. Exploratory endpoints included clinical outcomes and recurrence types. Results: The cohort was 82.9% male (n = 155). The most frequent tumor sites were the oral cavity (36.9%) and larynx (36.9%), with 55% (n = 103) diagnosed at stage IVA. Of 75 cases tested for p16, 35.3% (n = 36) were positive. The median time from symptom onset to diagnosis was 166.5 days (95% CI: 123.4–197.8) and from diagnosis to treatment 42 days (95% CI: 31.6–50.4). Initial treatments included surgery (36.4%), chemoradiotherapy (24.6%), induction chemotherapy (19.8%), supportive care (11.2%), and radiotherapy (8%). Locoregional control was achieved in 42.8% of patients, with an overall recurrence rate of 2.8%. Conclusions: This study provides real-world insights into the epidemiology and management of locally advanced HNSCC in Mexico, outlining the patient journey from initial symptoms to treatment and underscoring the need for more individualized therapeutic strategies based on molecular profiling and clinical characteristics.