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Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has improved outcomes in non-small cell lung cancer (NSCLC) patients harboring the T790M mutation; however, emerging clinical evidence indicates a risk of cardiotoxicity. Here, we establish the first in vivo preclinical model of osimertinib-induced cardiotoxicity using transverse aortic constriction (TAC) in mice. Osimertinib treatment resulted in cardiac dysfunction, impaired hypertrophic remodeling, and increased markers of heart failure and fibrosis. Unbiased transcriptomic profiling revealed a myocardial stress response characterized by activation of p53-associated cell death pathways, mitochondrial dysfunction, and negative enrichment of histone acetyltransferase (HAT) complexes, indicating epigenetic repression. Mechanistically, osimertinib-treated hearts exhibited increased expression of multiple histone deacetylase (HDAC) isoforms, reduced acetylation of histones, and enhanced cardiomyocyte apoptosis via Bax/caspase-mediated pathways. There was a minimal, transient effect on inflammation, supporting a type I, cell-autonomous cardiotoxic mechanism. Consistent with this, in vitro and in vivo analyses demonstrated suppression of prosurvival ERK/AKT signaling, mitochondrial dysfunction, and activation of intrinsic apoptotic pathways. Given the central role of HDAC activation, we tested whether pharmacologic HDAC inhibition could mitigate osimertinib-induced cardiotoxicity. Treatment with the FDA-approved HDAC inhibitor vorinostat (SAHA) restored histone acetylation, attenuated p53 activation, reduced cardiomyocyte death, and rescued cardiac function in osimertinib-treated mice. Translational studies in human NSCLC-derived PC9 cells further demonstrated that SAHA enhances osimertinib antitumor efficacy while alleviating cardiotoxicity. Collectively, these findings define HDAC-dependent epigenetic repression as a key mechanism underlying osimertinib-induced cardiotoxicity and identify HDAC inhibition as a therapeutically actionable strategy to improve both cardiac safety and cancer treatment efficacy.