Epigenetic alterations are crucial to oncogenesis and regulation of gene expression in non–small-cell lung carcinoma (NSCLC). DNA methylation (DNAm) biomarkers may provide molecular-level prediction of relapse risk in cancer. Identification of optimal treatment is warranted for improving clinical management of NSCLC patients. Using machine learning algorithm we identified 4 recurrence predictive CpG methylation markers (cg00253681/ART4, cg00111503/KCNK9, cg02715629/FAM83A, cg03282991/C6orf10) and constructed a risk score model that potently predicted recurrence-free survival and prognosis for patients with NSCLC (P = 0.0002). Integrating genomic, transcriptomic, proteomic and clinical data, the DNAm-based risk score was observed to significantly associate with clinical stage, cell proliferation markers, somatic alterations, tumor mutation burden (TMB) as well as DNA damage response (DDR) genes, and potentially predict the efficacy of immunotherapy. In general, our identified DNAm signature shows a significant correlation to TMB and DDR pathways, and serves as an effective biomarker for predicting NSCLC recurrence and response to immunotherapy. These findings demonstrate the utility of 4-DNAm-marker panel in the prognosis, treatment decision-making and evaluation of therapeutic responses for NSCLC.