Non-small cell lung cancer (NSCLC), the primary histological form of lung cancer, accounts for about 25%—the highest—of all cancer deaths. As NSCLC is often undetected until symptoms appear in the late stages, it is imperative to discover more effective tumor-associated biomarkers for early diagnosis. Topological data analysis is one of the most powerful methodologies applicable to biological networks. However, current studies fail to consider the biological significance of their quantitative methods and utilize popular scoring metrics without verification, leading to low performance. To extract meaningful insights from genomic data, it is essential to understand the relationship between geometric correlations and biological function mechanisms. Through bioinformatics and network analyses, we propose a novel composite selection index, the C-Index, that best captures significant pathways and interactions in gene networks to identify biomarkers with the highest efficiency and accuracy. Furthermore, we establish a 4-gene biomarker signature that serves as a promising therapeutic target for NSCLC and personalized medicine. The C-Index and biomarkers discovered were validated with robust machine learning models. The methodology proposed for finding top metrics can be applied to effectively select biomarkers and early diagnose many diseases, revolutionizing the approach to topological network research for all cancers.