Although the advent of osimertinib has brought revolutionary changes to the treatment landscape of non-small cell lung cancer (NSCLC) patients, acquired resistance remains a major obstacle limiting long-term survival benefits for the treatment of cancer. The purpose of this study was to examine the mechanisms involved in the ability of bazedoxifene to synergistically enhance osimertinib sensitivity, which will aid in delaying and overcoming osimertinib resistance to improve patient outcomes. Here, we found that osimertinib increased the production of reactive oxygen species (ROS), promoted mitochondrial fission, diminished mitochondrial membrane potential, and activated cell apoptosis. Moreover, the p-STAT3/suppressor of cytokine signaling 3 (SOCS3) and KEAP1/NRF2 signaling pathways were activated to scavenge ROS and promote osimertinib resistance. Mechanistically, SOCS3 can directly bind to KEAP1 to prevent the degradation of NRF2, resulting in the activation of an NRF2-dependent transcriptional program. Furthermore, the osimertinib-induced mitochondrial dysfunction and apoptosis were enhanced by bazedoxifene, thereby delaying and overcoming osimertinib resistance by inhibiting these pathways in vitro and in vivo. These findings identified a new critical link in the p-STAT3/SOCS3 pathway, KEAP1/NRF2 pathway, mitochondrial dysfunction, and osimertinib resistance. The present study demonstrated that bazedoxifene can be used for delaying or overcoming osimertinib resistance in NSCLC.Copyright © 2023 Elsevier Inc. All rights reserved.