Redox imbalance, including excessive production of reactive oxygen species (ROS) caused by mitochondrial dysfunction and insufficient endogenous antioxidant capacity, is the primary cause of myocardial ischemia‒reperfusion (I/R) injury. In the exploration of reducing myocardial I/R injury, it is found that protecting myocardial mitochondrial function after reperfusion not only reduces ROS bursts but also inhibits cell apoptosis triggered by the release of cytochrome c. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2) is considered a potential therapeutic target for treating myocardial I/R injury by enhancing the cellular antioxidant capacity through the induction of endogenous antioxidant enzymes. In this study, a peptide‒drug conjugate OI-FFG-ss-SS31(ISP) is developed by integrating the Nrf2 activator 4-octyl itaconate (OI) and the mitochondria-targeting protective peptide elamipretide (SS31), and its therapeutic potential for myocardial I/R injury is explored. The results showed that ISP could self-assemble into nanofibers in response to the acidic microenvironment and bind to Keap-1 with high affinity, thereby activating Nrf2 and enhancing antioxidant capacity. Simultaneously, the release of SS31 could improve mitochondrial function and reduce ROS, ultimately providing a restoration of redox homeostasis to effectively alleviate myocardial I/R injury. This study presents a promising acid-triggered peptide-drug conjugate for treating myocardial I/R injury.