Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous group of malignancies with poor survival outcomes, particularly in advanced stages. Identifying prognostic biomarkers could help improve patient management. miR-375, a small non-coding RNA, has been shown to influence tumor growth and immune responses, making it a candidate biomarker. This study aims to evaluate the role of miR-375 expression in predicting survival outcomes in HNSCC patients. A systematic review and meta-analysis were conducted according to PRISMA guidelines, incorporating data from six studies and the TGCA cohort, encompassing 452 patients. Fixed-effects models were applied to calculate aggregated hazard ratios (HRs) for overall survival (OS). Kaplan-Meier curves were analyzed using the Tierney method, and Trial Sequential Analysis (TSA) was performed to assess statistical power. Low miR-375 expression was associated with poorer OS, with an aggregated HR of 1.23 (95% CI: 1.10-1.37). Subgroup analysis showed consistent trends across oral and laryngeal squamous cell carcinoma. Sensitivity analysis confirmed these findings. TSA revealed that although the number of patients was sufficient, statistical power was insufficient to confirm a predefined risk reduction ratio (RRR) of 49%. Data from the TGCA cohort supported the meta-analysis findings, with an HR for OS of 1.32 (95% CI: 0.96-1.8). Low miR-375 expression is associated with worse survival outcomes in HNSCC patients, indicating its potential as a prognostic biomarker and therapeutic target. However, the retrospective nature of the included studies underscores the need for prospective research to validate these findings.