Epithelial-mesenchymal transition (EMT) is clinically associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small cell lung cancers (NSCLC). However, the mechanisms promoting EMT in EGFR TKI-resistant NSCLC have not been fully elucidated. Previous studies have suggested that IGF1R signaling is involved in both acquired EGFR TKI resistance in NSCLC and induction of EMT in some types of tumor. In this study, we further explored the role of the IGF1R signaling in the acquisition of EMT phenotype associated with EGFR TKI resistance in mutant-EGFR NSCLC. Compared to gefitinib-sensitive parental cells, gefitinib-resistant (GR) cells displayed an EMT phenotype associated with increased migration and invasion abilities with the concomitant activation of IGF1R and NF-κB p65 signaling. Inhibition of IGF1R or p65 using pharmacological inhibitor or specific siRNA partially restored sensitivity to gefitinib with the concomitant reversal of EMT in GR cells. Conversely, exogenous IGF1 induced both gefitinib resistance and accompanying EMT in parental cells. We also demonstrated that IGF1R could phosphorylate downstream Akt and Erk to activate NF-κB p65. Taken together, our findings indicate that activation of IGF1R/Akt/Erk/NF-κB signaling is linked to the acquisition of EGFR TKI resistance and EMT phenotype in EGFR-mutant NSCLC and could be a novel therapeutic target for advanced NSCLC.