This study aimed to investigate the potential pathogenesis of early non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), by constructing a global transcriptional regulatory landscape to identify hub genes and key pathways. A total of 1,206 differentially expressed genes (DEGs) in early NSCLC were identified compared to normal lung tissue samples in GSE33532 and GSE29013. DEGs-related protein-protein interaction networks (PPIs) were constructed based on the STRING database and were then modularly analyzed using the ClusterOne tool. The enrichment analysis revealed that multiple modules were significantly involved in pathways such as the TNF signaling pathway, PPAR signaling pathway and PI3K/AKt signaling pathway. Ten genes were identified as hub genes in the PPIs and also found up-regulated at protein level. The prognostic value of the hub genes and the ten hub gene set variation score varied according to the different pathological types of NSCLC, which suggested the ten hub gene expression patterns can reflect the heterogeneity of two types of NSCLC. In conclusion, by carrying out a series of in-depth analyses, hub genes and key pathways associated with early NSCLC were identified by a global transcriptional regulatory landscape.