Takotsubo syndrome (TTS), once considered benign, can cause life-threatening myocardial injury. Although oxidative stress and ferroptosis are implicated in its pathogenesis, targeted therapies are not available for TTS. We demonstrate that sulforaphane (SFN), a natural Nrf2 activator, mitigates TTS-related injury in isoproterenol-induced rat models and AC16 cardiomyocytes. Isoproterenol induced ferroptosis and oxidative stress by impairing Nrf2 signaling. SFN treatment restored myocardial structure and function while enhancing antioxidant capacity, reducing mitochondrial damage, and suppressing ferroptosis markers. Additionally, similar to Fer-1 (a ferroptosis inhibitor), SFN reduced intracellular ferrous levels but uniquely activated Nrf2-driven endogenous defenses. Notably, Nrf2 inhibition abrogated the benefits of SFN in both in vitro and in vivo experiments. These findings highlight SFN as a dual-action therapeutic for TTS, simultaneously targeting oxidative stress and ferroptosis via Nrf2 activation. The therapeutic efficacy of SFN, combined with endogenous pathway modulation, underscores its translational potential for improving TTS outcomes.