OBJECTIVES: This study aims to investigate the protective effects of thymoquinone and melatonin on the heart against doxorubicin-induced cardiotoxicity in rats. BACKGROUND: Melatonin and thymoquinone may play an important role in cardiotoxicity. METHODS: The subjects were divided into four groups: Control (physiological serum on 5th day), Doxorubicin (DXR), Doxorubicin+Melatonin (DXR+MEL, 10 mg/kg melatonin, intraperitoneally), and Doxorubicin+Thymoquinone (DXR+TQ, 50 mg/kg thymoquinone, orally). On the 5th day of the experiment, all groups were injected with 45 mg/kg DXR into the tail vein. On the 8th day of the experiment, ECG recordings were performed under anaesthesia. RESULTS: Thymoquinone reduced the PR, QRS and QTc intervals, which were increased by DXR, while melatonin only reduced the QTc interval. Melatonin had a protective effect against the histopathological changes induced by DXR, while TQ did not demonstrate such an effect. DXR increased CK-MB, IL-6, MDA, IL-1, IL-18 levels and decreased SOD in the cardiac tissue. MEL reduced the levels of CK-MB, MDA, NO, SOD, IL-1, IL-6, IL-18. Meanwhile, TQ only reduced CK-MB, IL-1 and IL-18. CONCLUSION: Our study showed that DXR induces cardiac injury and that melatonin improves biochemical parameters and offers histological protection; while thymoquinone improves ECG parameters and causes partial recovery of biochemical parameters (Tab. 4, Fig. 2, Ref. 41).