Doxorubicin (DOX), a widely used chemotherapeutic, is significantly limited by dose-dependent cardiotoxicity characterized by oxidative stress, mitochondrial dysfunction, and ferroptosis. Despite decades of research, dexrazoxane (DXZ) remains the only approved cardioprotectant, yet its clinical utility is constrained by potential reduction in efficacy and systemic toxicity. Effective alternatives are therefore urgently needed. Through high-throughput screening of a 960-compound natural product library, we identified arctigenin (ATG), a major bioactive compound from the Asian medicinal plant Arctium lappa L., as a promising cardioprotective candidate against DOX-induced cardiotoxicity (DIC). Both in vitro and in vivo studies demonstrated that ATG significantly attenuated DOX-induced cell death, reduced ROS accumulation, inhibited ferroptosis, preserved mitochondrial function, and improved cardiac function and myocardial structural integrity in mice. Mechanistically, ATG activated the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway by binding to the serine 602 residue of Kelch-like ECH-associated protein 1 (KEAP1), which competitively inhibited the KEAP1-NRF2 interaction. This binding facilitated the dissociation of NRF2 from KEAP1, resulting in reduced NRF2 ubiquitination, increased nuclear accumulation of NRF2, and enhanced transcription of downstream target genes. Collectively, our results identify ATG as a novel NRF2 activator that alleviates DIC through suppression oxidative stress and ferroptosis by directly targeting the KEAP1-NRF2-ARE axis.