Abstract Objective To design melatonin (Mel)-based nanomedicines (Mel-NMs) and evaluate their therapeutic effects on myocardial ischemia reperfusion injury in mice. Methods Melatonin self-assembled peptides (Mel-NMs) were synthesized by incorporating the GFFY peptide and a cardiac targeting peptide (CTP), and their structure was characterized using transmission electron microscopy. A myocardial ischemia reperfusion injury model was established in mice by ligating the left anterior descending coronary artery for 30 minutes, followed by reperfusion. Mice were randomly divided into five groups: sham operation, model, Mel, NMs, and Mel-NMs. Treatment was administered intraperitoneally 10 minutes prior to reperfusion, with Mel (5 mg/kg), NMs, or Mel-NMs (containing Mel 5 mg/kg) or an equal volume of solvent for the sham group. Twenty-four hours after reperfusion, cardiac function, apoptosis, and oxidative stress markers were assessed. Results Transmission electron microscopy revealed that Mel-NMs formed worm-like structures. Compared to the sham group, the model group exhibited significantly reduced cardiac function (P < 0.05), increased serum LDH levels, elevated cardiomyocyte apoptosis (P < 0.05), decreased GSH-Px and SOD activities, and increased MDA content (P < 0.05). Treatment with Mel and Mel-NMs significantly improved cardiac function, reduced LDH and MDA levels, and enhanced GSH-Px and SOD activities (P < 0.05), while also decreasing cardiomyocyte apoptosis (P < 0.05). Notably, the Mel-NMs group demonstrated superior outcomes compared to the Mel group in improving cardiac function and reducing oxidative stress and apoptosis levels (P < 0.05). Conclusion Mel-NMs effectively mitigate myocardial oxidative stress and apoptosis, offering a more potent cardioprotective effect than Mel alone.