Background and aims: The consumption of grape seed nanoparticles extract can control cardiovascular risk factors. Exercise plays a protective role against cardiovascular disease. Therefore, the aim of the present study was to investigate the effect of eight-week resistance training (RT) and the use of grape seed nanoparticles on mitochondrial biogenesis of heart tissue in myocardial infarction (MI) models. Methods: In this experimental study, 25 rats were randomly divided into five groups including (1) control (C), (2) MI, (3) MI+RT, (4) MI+grape seed, and (5) MI+RT+grape seed. MI was induced by subcutaneous injection of isoprenaline (85 mg/kg). Grape seed nanoparticles were daily administered at a dose of 150 mg/kg for 8 weeks, and RT was performed 5 days a week. Finally, data were analyzed using the one-way analysis of variance (ANOVA) and Tukey’s post hoc tests (P≤0.05). Results: MI models showed decreased expression of PGC-1α, PPARγ, and UCP-1 genes in cardiac tissue (P=0.001). However, RT combined with the use of grape seed nanoparticles had a significant effect on increasing the expression of PGC-1α (P=0.001), PPARγ (P=0.002), and UCP-1 (P=0.003) genes in the heart tissue of MI model mice. Conclusion: The consumption of grape seed nanoparticles along with RT has more effects on improving the expression of PGC-1α, PPARγ, and UCP-1 genes in MI than either alone. Therefore, the use of grape seed nanoparticles together with RT is recommended in case of MI.