Lung cancer is a widely occurring and deadly malignancy, with high prevalence rates in China and across the globe. Specifically, non-small cell lung cancer (NSCLC) represents about 85% of all lung cancer cases. The 5-year disease-free survival rate after surgery for stage IB-IIIB NSCLC patients (disease-free survival, DFS) has notably declined from 73% to 13%. Early detection of abnormal cancer molecules and subsequent personalized treatment plans are the most effective ways to address this problem. Liquid biopsy, surprisingly, enables safe, accurate, non-invasive, and dynamic tracking of disease progression. Among the various modalities, circulating tumor DNA (ctDNA) is the most commonly used liquid biopsy modality. ctDNA serves as a credible “liquid biopsy” diagnostic tool that, to a certain extent, overcomes tumor heterogeneity and harbors genetic mutations in malignancies, thereby providing early information on tumor genetic alterations. Despite considerable academic interest in the clinical significance of ctDNA, consensus on its utility remains lacking. In this review, we assess the role of ctDNA testing in the diagnosis and management of NSCLC as a reference for clinical intervention in this disease. Lastly, we examine future directions to optimize ctDNA for personalized therapy.