Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolar disorder.However, it has a narrow therapeutic index with toxic effects on various organs. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxic effects of lithiumon the heart of adult albino rats and its molecularmechanisms and the ameliorating effect ofNacetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated receivedNAC500 mg/kg/week dissolved in 1 ml 0.9% sodiumchloride intraperitoneal, lithium-treated received 52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NACtreated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB(CK-MB), cardiac troponin I (cTnI), and several histological lesions with a significant increase in the area% of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-20-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlated to the area%of VanGieson staining.NACsignificantly improved the cardiotoxic effects of lithium. Being a nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.