Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is the most prevalent form, accounting for nearly 95% of laryngeal cancer. This study evaluates the effectiveness of chemotherapy and radiation therapy combined for treating LSCC, along with exploring miR-449a as a potential biomarker for predicting treatment response and prognosis in LSCC patients. Patients and Methods: The study had 81 patients with advanced laryngeal cancer and 50 healthy controls. Chemotherapy was given for two cycles, followed by an evaluation of the response. Disease progression cases had surgical resection and radiation therapy. Positive responders had radiation therapy after a third cycle. The study also assessed miR-449a expression levels in tumor tissue, normal tissue, and serum samples from control subjects. Results: 31% achieved a complete response, and 49% showed a partial response. 31% of complete response participants maintained laryngeal integrity and vocal function. After radiation therapy, 74% of 65 patients responded completely and preserved laryngeal functions. Lower MiR-449a levels found in LSCC tissues and serum samples were correlated with aggressive tumor behavior, poor prognostic markers, and decreased survival. Conversely, elevated levels were seen in treatment responders. Conclusions: Combined chemo and radiotherapy preserve vocal function and improve outcomes in LSCC. MiR-449a is a promising indicator for diagnosis and treatment efficacy in LSCC.