Introduction The gut microbiome (GM) has been implicated in cancer pathogenesis and treatment, including head and neck cancers (HNC). However, the specific microbial compositions influencing HNC and the underlying mechanisms remain largely unknown.Methods This study utilized published genome-wide association studies (GWAS) summary data-based two-sample Mendelian randomization (MR) to uncover the GM compositions that exert significant causal effects on HNC. Functional annotation and enrichment analysis were conducted to better understand the significant genetic variables and their connection with HNC. The HNC dataset included 2,281 cases and 314,193 controls. The GM GWAS data of 211 gut taxa (35 families, 20 orders, 16 classes, 9 phyla, and 131 genera) were obtained from the MibioGen consortium, involving 18,340 participants.Results MR analysis revealed four GM compositions exerting causal effects on HNC. Specifically, family Peptococcaceae.id.2024 was significantly associated with a 35% reduced risk of HNC (OR=0.65; 95%CI=0.48-0.90; P=0.0080). In contrast, genus DefluviitaleaceaeUCG-011.id.11287 (OR=1.54; 95%CI=1.13-2.09; P=0.0060), genus Gordonibacter.id.821 (OR=1.23; 95%CI=1.05-1.45; P=0.012), and genus Methanobrevibacter.id.123 (OR=1.28; 95%CI=1.01-1.62; P=0.040) showed a significant association with an increased risk of HNC. These GMs interact with genes and genetic variants involved in signaling pathways, such as GTPase regulation, influencing tumor progression and disease prognosis.Conclusions Our study demonstrates, for the first time, the causal influence of specific gut microbiome compositions on HNC, offering significant insights for advancing clinical research and personalized treatments. The identified GMs may serve as potential biomarkers or therapeutic targets, paving the way for innovative approaches in HNC diagnosis, prevention, and therapy.