Long-term exposure to nicotine accelerates the development and the progression of cardiovascular disease in smokers through cardiac damage. This research aims to investigate the ameliorative effects of melatonin and captopril in rats exposed to nicotine and report the effect of nicotine withdrawal. Sixty male rats were divided into 6 groups. A control group received saline, nicotine group received nicotine (1 mg/kg). The four other groups were administered melatonin (10 mg/kg), captopril (100 mg/kg), or a combination of melatonin and captopril, and a last group that received nicotine followed by 28 days of nicotine withdrawal. In all groups, biochemical parameters of cardiac toxicity in addition to evaluation of caspase-3 and TNF-α in cardiac tissue by immunohistochemistry were estimated. Administration of nicotine induced significant oxidative damaging effects as reflected by significant lowering of SOD, CAT and GPx levels and significant elevation of cardiac NO and MDA levels compared to control group. Furthermore, cardiac damage and collagen deposition were reported by histological and immunohistochemical evaluation. Treatment with captopril and melatonin reduced nicotine-induced biochemical disturbances and histological damage. Treatment with melatonin is superior to captopril on several parameters and nicotine withdrawal recorded the best ameliorating effect.