Lung cancer is the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and over 60% express wild-type EGFR (WT-EGFR); however, EGFR tyrosine kinase inhibitors (TKIs) have limited effect in most patients with WT-EGFR tumors. In this study, we applied network pharmacology screening and MTT screening of bioactive compounds to obtain one novel grifolic acid that may inhibit NSCLC through the EGFR-ERK1/2 pathway. Through the PPI network and machine learning, we identified two hub genes, EGFR and AKT1, as potential therapeutic targets. Molecular docking confirmed that the grifolic acid could effectively bind to the key target, EGFR. Using the NSCLC cell line NCI-H1781 as an in vitro model, we evaluated the effect of the drugs' combination on viability, apoptosis, and clonogenicity capacity. In vitro studies showed that combined treatment decreased cell viability, increased activation PARP, and caused cell cycle redistribution and significantly greater inhibition of pEGFR and pAKT. This study not only provides new insights into the mechanism of grifolic acid against NSCLC but also important information and new research ideas for the discovery of anti-NSCLC compounds from natural products.