Radiotherapy (RT) is integral to the management of head and neck squamous cell carcinoma (HNSCC), yet no validated biomarker exists to predict which patients benefit most. Lactylation, a metabolic post-translational modification, has been linked to DNA damage repair (DDR) and therapeutic resistance, but no lactylation-based radiosensitivity biomarker has been established in HNSCC. Here, we analyzed RNA-Seq and clinical data from 511 TCGA-HNSCC patients (308 RT, 203 non-RT) and constructed a three-gene lactylation-related radiosensitivity index (LRSI) comprising CARS2, KARS1, and BCL6 via treatment-stratified gene selection and LASSO-Cox regression. Radiosensitive (RS) patients derived significant RT benefit (HR = 0.45, 95% CI 0.30–0.67, P < 0.001), whereas radioresistant (RR) patients did not (HR = 0.98, P = 0.93; P_interaction = 0.0035). These results were robust across propensity score matching, inverse probability of treatment weighting, HPV-adjusted, and surgery/chemotherapy-adjusted analyses. In the independent GSE67614 post-RT cohort (n = 102), the LRSI discriminated locoregional recurrence with an AUC of 0.73 (adjusted OR = 2.05, P = 0.013). Biological characterization revealed that RR tumors exhibited elevated DDR activity, reduced immune infiltration, and heightened senescence-associated secretory phenotype. The LRSI is a predictive signature linking lactylation, DDR, and the tumor immune microenvironment to differential RT benefit in HNSCC. Prospective validation is warranted.