Nanotechnology provides a cost-effective way to apply commercial-level metal-oxidizing nanoparticles that are used as cardioprotective agents. Innovative nanoparticle transactions could transform medical cardioprotective devices. Nanostructured materials have unique physical and chemical properties promising for cardiovascular equipment. Among the interesting features are narrow size, high surface area, high reactivity, high biological interaction and functional structure. In this study, we prepared, characterized, and investigated the cardioprotective effects of copper nanoparticles green-formulated by Berberis vulgaris leaf extract. In characterization, fourier-transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), ultraviolet–visible spectroscopy (UV-Vis), and transmission electron microscopy (TEM) were applied. In the in vivo design, isoproterenol (40 mg/kg) was administered to induce myocardial ischemia in C57BL/6 mice. Copper nanoparticles at different doses (15, 30 and 60 μg/ml) were used for the treatment of mice. Copper nanoparticles exerted cardioprotective properties against isoproterenol-induced myocardial ischemia in mice, which may associated to the peroxisome proliferator-activated receptor gamma (PPAR-γ) activation and nuclear factor kappa B (NF-κB) signaling inhibition. The copper nanoparticles beneficial effects were related to the normalization in PPAR-Υ and PPAR-Υ/NF-κB/ΙκB-α/ΙΚΚα/β phosphorylation gene expression. Treatment with copper nanoparticles significantly suppressed the inflammation cytokines expression and decreased cell death. Also, copper nanoparticles administration significantly prevented the typical ST segment depression. In addition, copper nanoparticles treatment significantly ameliorated ventricular wall ischemia, reduced the mortality incidence, and inhibited the myocardial injury markers levels. Copper nanoparticles treatment decreased the inflammatory milieu in the myocardial ischemia mice heart, thereby blocking the proinflammatory cytokines upregulation (interleukin-1β (IL-1β), tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6)). After doing the clinical trial studies, the recent copper nanoparticles can be used as a novel cardioprotective drug in human.