Inflammation seems to play a critical role in the development and progression of different cancers. Neutrophil-to-lymphocyte ratio (NLR) is an easily measurable marker of systemic inflammation. The purpose of this systematic review and meta-analysis was to evaluate the prognostic role of the pre-treatment neutrophil-to-lymphocyte ratio (NLR), in terms of overall survival (OS) and disease-free survival (DFS), in patients with primary head and neck squamous cell carcinoma (HNSCC) treated by surgery alone or followed by chemo/radiotherapy. This systematic review was performed according to the guidelines reported in the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Meta-analysis of overall survival and disease-free survival was performed using the inverse of variance test. Fixed-effect models were used on the basis of the presence of heterogeneity. Risk of bias assessment and trial sequential analysis (TSA) were also performed; the quality of the evidence was evaluated via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The analysis revealed that a higher value of pre-treatment NLR correlates with a statistically significant decrease of overall survival (HR, 1.56; 95% CI: [1.35, 1.80]; P<0.00001) and a lower disease-free survival (HR, 1.64; 95% CI: [1.30, 2.07]; P<0.0001) in HNSCC patients.