Biomarkers are increasingly used in cancer management, including lung cancer. The use of circulating tumour DNA (ctDNA) detection has attracted significant interest as a non-invasive, highly specific, and sensitive strategy. In this study, we developed and validated a methylation-specific droplet digital PCR (ddPCR) multiplex assay with five tumour-specific methylation markers identified by in silico analysis for lung cancer detection across various clinical settings. The performance of the ddPCR multiplex was validated in tissue and plasma in cohorts of healthy controls and patients with both non-metastatic and metastatic disease by examining sensitivity, specificity, and marker dynamics. Furthermore, two different cut-off methods to determine ctDNA-status and their effects on sensitivity and specificity were examined. In non-metastatic disease, the ddPCR multiplex showed ctDNA-positive rates of 38.7% and 46.8%, respectively, with the two cut-off methods. In metastatic cases, these rates increased to 70.2% and 83.0%. Higher sensitivities were observed for small cell lung cancer and squamous cell carcinoma. Analyses of longitudinal samples from patients with metastatic disease undergoing treatment indicated a potential use in prognostication and treatment guidance. We present a robust, cost-effective approach to lung cancer detection. Moving forward, its performance should be evaluated and validated in larger patient cohorts across a range of clinical scenarios, exploring its full potential.