Background: Zinc Oxide nanoparticles (ZnO NPs) are broadly utilized in medications, foodstuffs, cosmetics plus toothpastes. Studies have shown that the heart is one of the target organs following oral exposure to ZnO NPs. N-acetylcysteine (NAC) is a free radical scavenger, used to combat damage in various tissues. This research was performed to define the mechanistic hypothesis of ZnO NPs induced cardiotoxicity and the possible protective role of NAC. Methods: The research was performed on 40 adult albino rats; divided into 5 groups each of 8 rats, group I as a negative control, group II (positive control) received distilled water, group III (NAC group) received (200 mg/kg) NAC dissolved in distilled water, group IV (ZnO NPs group): received (422 mg/kg) ZnO NPs dissolved in distilled water, group V (NAC and ZnO NPs group): received NAC then ZnO NPs in the same doses. The treatments were given via oral gavage, once daily for 4 weeks. Results: There was a significant increase in mean values of cardiac enzymes and a significant decline in the total antioxidant capacity in ZnO NPs treated group as compared with the control group. DNA fragmentation was observed in heart tissues of ZnO NPs treated group. Histological examination of the heart of ZnO NPs treated group revealed degenerated myocardium, vacuolated cytoplasm, and congestion in myocardial blood vessels when compared with control group. Conclusion: Administration of NAC offered protection against cardiotoxic effects induced by ZnO NPs.