The present study was carried out to determine histopathological effects of nicotine, one of the most significant components of tobacco, on mouse liver and ameliorative effect of melatonin on liver damage. A total of 140 mature Swiss Albino mice (Mus musculus) were divided into four experimental groups: control group, nicotine group, melatonin group and nicotine+melatonin group. Each group was further subdivided into seven groups (five mice each) according to the time of killing (12h and days 1, 3, 5, 7, 14 and 21 after drug administration). In nicotine and nicotine+melatonin groups, 3mg/kg of nicotine was injected intraperitoneally every day until killing. The nicotine+melatonin group was additionally injected with 10mg/kg of melatonin after 30min of nicotine injection. The melatonin group was injected only with 10mg/kg of melatonin every day until killing. All the treatments were given 2h before sunset, when melatonin receptors were active. After the last injection, five mice from each group were killed at 12th hour and on days 1, 3, 5, 7, 14 and 21; the livers were removed for histopathological processing by light microscopy. The histopathological results revealed time-dependent degeneration in the livers of mice in nicotine group. Regenerative changes in the nicotine and melatonin groups were observed when compared with nicotine groups.