BACKGROUND/AIM: NSCLC severity is driven by dysregulation of the EGFR/PI3K/Akt pathway, promoting tumor growth and drug resistance. Hyperactive EGFR/PI3K/Akt signaling results in aggressive tumors and poor patient outcomes, worsened by resistance to EGFR inhibitors. Therefore, targeting this pathway may inhibit tumor growth and induce resistance. Artogomezianone, a compound derived from , has shown considerable anti-cancer efficacy, mainly by inducing apoptosis and decreasing the proliferation of several cancer types. In this study, artogomezianone was investigated regarding its inhibitory effects on the EGFR/PI3K/Akt pathway. MATERIALS AND METHODS: Cytotoxicity and primarily apoptotic induction effects were examined by the MTT assay and Hoechst 33342 and propidium iodide staining and confirmed by western blot analysis. In addition, western blot analysis and molecular docking were used to determine the protein levels and binding affinity of compound and significant proteins in EGFR/PI3K/Akt pathway. RESULTS: Artogomezianone showed cytotoxicity and apoptotic induction effects against A549 (NSCLC) cells. It increased the cleavage of PARP and decreased procaspase-9 protein levels. In the EGFR/PI3K/Akt pathway, artogomezianone caused significant decrease in p-PI3K/PI3K and p-Akt/Akt protein levels. Moreover, molecular docking analysis showed that artogomezianone could bind EGFR ATP-binding site with greater affinity than erlotinib, the formal EGFR inhibitor. CONCLUSION: For the first time, it was demonstrated that artogomezianone has an anti-cancer effect via direct interaction with EGFR proteins in the EGFR/PI3K/Akt pathway and causes the inhibitory effects of its downstream proteins (PI3K and Akt), resulting in an induction of NSCLC apoptosis.