Treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC) using mutation-selective third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib has achieved remarkable success. However, the emergence of acquired resistance is an inevitable challenge that limits the long-term remission of patients. Thus, it is critical to manage acquired resistance to osimertinib to maximize its therapeutic efficacy for long-term therapeutic benefit. To this end, taking an early intervention to delay or even prevent the emergence of acquired resistance to osimertinib offers an effective strategy. The current study suggests an effective strategy to do so through directly targeting the intrinsic apoptotic pathway via Mcl-1 inhibition. Several EGFR-mutant NSCLC cell lines with primary resistance to osimertinib possessed elevated levels of Mcl-1, which were no longer reduced by osimertinib. The combination of osimertinib with an Mcl-1 inhibitor (e.g., S63845 or APG3526) synergistically decreased the survival of these resistant cell lines with enhanced induction of apoptosis including augmentation of mitochondrial cytochrome C and Smac release. This combination effectively eliminated senescence-like drug-tolerant persister cells, which had elevated Mcl-1 levels, and abrogated emergence of acquired resistance to osimertinib as demonstrated using both in vitro cell culture and in vivo animal models. Collectively, these results convincingly demonstrate a novel and effective strategy for delaying the emergence of acquired resistance to osimertinib by targeting activation of the intrinsic apoptotic pathway through Mcl-1 inhibition, warranting further clinical validation of this strategy.Copyright © 2025. Published by Elsevier B.V.