The present study was carried out to investigate the ameliorative effects of melatonin against nicotine-induced heart and lung toxicity. For this purpose, 75 mature male Sprague Dawley (SD) rats weighing 150-170 g were randomly divided into five groups (15 rats each): control group (rats were I/P injected with 1% ethanol in saline), nicotine group (rats were I/P injected with 0.6 mg/kg body weight), and combined nicotine and melatonin groups (rats received nicotine as in the previous group and melatonin at a dose of 1, 5, or 10 mg/kg body weight, respectively); all treatments were continued for 21 days. Fasting blood samples were collected from each rat at the 11th day and one day after the end of the last injection (22nd day) for complete blood count (CBC) determination, while sera were collected for the determination of lipid profiles. Malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, and reduced glutathione (GSH) as well as DNA fragmentation percentage were assessed in cardiac tissue. Heart and lung samples were collected for estimation of caspase-3 expression and histopathological examination. The results revealed that nicotine increased the number of RBCs, Hb concentration, total cholesterol, and low density lipoprotein (LDL) and decreased high density lipoprotein (HDL). In addition, it decreased SOD activity and GSH concentration with increased MDA concentration, and DNA fragmentation in the heart, as well as caspase-3 expression in both heart and lungs. It also induced histopathological changes in the heart and lung tissues. Melatonin could ameliorate the deleterious effect of nicotine on the previous parameters either partially or completely, where melatonin restored complete blood count, improved lipid profile, mended lipid peroxidation and antioxidant parameters in the cardiac tissue, rectified caspase-3 expression in the heart and lungs, ameliorated DNA fragmentation percentage in the heart, and protected both heart and lung tissue against the harmful effect of nicotine. It is concluded that melatonin has a protective effect on the heart and lungs against the harmful effect of nicotine.