A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutant lung cancer. While epithelial-to-mesenchymal transition (EMT) plays a role in the resistance to various targeted drugs, its involvement in EGFR-inhibitor resistance remains largely unknown. Pre-clinical experiments with osimertinib-resistant lung cancer cells showed that EMT was associated with decreased miR-200c and increased ZEB1 expression. In several resistant clone cells, pre-treatment with the histone deacetylase (HDAC) inhibitor quisinostat helped overcome the resistance by reverting EMT. Furthermore, drug screening from a library of 100 kinase inhibitors indicated that GSK-3 inhibitors, such as LY2090314, markedly inhibited the growth and induced apoptosis of resistant cells, specifically those with a mesenchymal phenotype. These results suggest that GSK-3 inhibition may be useful to circumvent EMT-associated resistance to osimertinib in EGFR mutant lung cancer.