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 and their structure was characterized by transmission electron microscopy. Mice were divided randomly into five groups: Sham, Model, Mel, NMs, and Mel-NMs, and a myocardial ischemia-reperfusion injury model was established. Mel (5 mg/kg), NMs, or Mel-NMs (containing Mel 5 mg/kg) were administered intraperitoneally 10 minutes prior to reperfusion, and the sham group was treated with an equal volume of solvent. Cardiac function, apoptosis, and oxidative stress markers were assessed 24 hours after reperfusion. Results Transmission electron microscopy revealed that Mel-NMs formed worm-like structures. Treatment with Mel and Mel NMs significantly improved cardiac function, reduced lactate dehydrogenase and malondialdehyde levels, and enhanced glutathione peroxidase and superoxide dismutase activities (P<0.05), while also decreasing cardiomyocyte apoptosis (P<0.05), with greater effects in the Mel-NMs group (P<0.05). Conclusions Mel-NMs can effectively mitigate myocardial oxidative stress and apoptosis, offering a more potent cardioprotective effect than Mel alone.