Recent years, cardiac vascular disease has arisen owing to acute myocardial infarction (MI) and heart failure leading to death worldwide. Various treatments are available for MI in modern medicine such as implantation of devices, pharmaceutical therapy, and transplantation of organs, nonetheless, it has many complications in finding an organ donor, devices for stenosis, high intrusiveness and long-time hospitalization. To overcome these problems, we have designed and developed a novel hydrogel material with a combination of Se NPs loaded poly(ethylene glycol)/tannic acid (PEG/TA) hydrogel for the treatment of acute MI repair. Herein, Se NPs were characterized by effective analytical and spectroscopic techniques. In vitro cell compatibility and anti-oxidant analyses were examined on human cardiomyocytes in different concentrations of Se NPs and appropriate Se NPs loaded hydrogel samples to demonstrate its greater suitability for in vivo cardiac applications. In vivo investigations of MI mice models injected with Se hydrogels established that LV wall thickness was conserved significantly from the value of 235.6 µm to 390 µm. In addition, the relative scar thickness (33.6%) and infarct size (17.1%) of the MI model were enormously reduced after injection of Se hydrogel when compared to the Se NPs and control (MI) sample, respectively, which confirmed that Se introduced hydrogel have greatly influenced on the restoration of the infarcted heart. Based on the investigated results of the nanoformulation samples, it could be a promising material for future generations treatment of acute myocardial infarction and cardiac repair applications.