Introduction: Doxorubicin is a highly effective anticancer agent with serious cardiotoxic effects. Hypertension is considered as a major risk factor for doxorubicin cardiotoxicity. It should be noted that about one-third of cancer patients have hypertension, and melatonin can have cardio-protective effects. The present study aimed to further investigate the possible beneficial effects of melatonin co-administration to perindopril against doxorubicin cardiotoxicity in hypertensive rats. Method: Rats were randomly assigned to naïve group and N-Omega-Nitro-L-Arginine Methyl Ester Hydrochloride (L-NAME) hypertensive group. L-NAME group was further subdivided into untreated, doxorubicin, doxorubicin / perindopril, doxorubicin/melatonin and doxorubicin/ perindopril / melatonin subgroups. Cardiac functions, CK-MB, malondialdehyde, superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and cardiac percentage area of collagen fibers were evaluated. Results: Combining melatonin with perindopril to doxorubicin produced significant decreases in left ventricular end diastolic pressure, malondialdehyde, TNF-α, and TGF-β. It resulted in significant increases in left ventricular dP/dtmax and SOD, in addition to apparent improvement in cardiac histopathology with a significant decrease in percentage area of collagen deposition compared to perindopril alone. Conclusion: Co-administration of melatonin to perindopril in hypertensive rats who received doxorubicin alleviated doxorubicin cardiac toxicity more than using perindopril alone. These effects could be explained by the reported antihypertensive, anti-inflammatory, anti-oxidant, and anti-fibrotic effects of melatonin.