Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is a common malignancy with unsatisfactory survival rates, highlighting the need for reliable biomarkers to improve diagnosis and prognosis. Growth differentiation factor 15 (GDF15), a protein implicated in various cancers, has not been thoroughly investigated in LSCC. This study aimed to evaluate the significance of GDF15 expression in LSCC and its potential clinical implications. Methods: We analyzed archival tissue samples from 65 LSCC patients using immunohistochemistry and evaluated GDF15 expression profiles from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Statistical analyses included Kaplan-Meier survival analysis and Cox proportional hazards regression to assess the correlation between GDF15 expression, clinicopathological variables, and survival outcomes. Results: GDF15 expression showed no significant difference between tumor and adjacent normal tissues. However, in the tissue macroarray (TMA) cohort, high GDF15 expression was significantly associated with lower TNM stage and less advanced pT status. Kaplan-Meier analysis revealed that high GDF15 expression correlated with poorer overall survival in the TMA cohort but not in the TCGA or GEO datasets. Multivariable analysis identified GDF15 as an independent prognostic factor for disease-free survival in LSCC. Conclusions: Our findings suggest that GDF15 may serve as a prognostic biomarker in LSCC, particularly in early-stage disease. Further research is warranted to validate these results and explore GDF15's potential as a therapeutic target, contributing to improved patient management.