Liver toxicity occurs when liver develops inflammation due to exposure to several toxic substances. The study was aimed to assess the liver damage induced by kainic acid and subsequently protective role of exogenous melatonin against the liver toxicity. Interestingly, kainic acid caused severe liver damage as evident from deleterious alterations in liver histology, increased lipid peroxide levels, decrease in the activities of liver anti-oxidant enzymes, DNA damage (adduct formation and sequence alterations), increased expression of cytokines like monocyte chemoattractant protein-1, interleukin 6, interferon γ and decreased expression of interleukin 10. These changes were normalized by melatonin (0.5-1.0 mM, (in vitro) or 10–20 mg/kg, (in vivo)). The study included assessment of the expression of immune modulatory cytokine mediators using real time PCR in both in vitro and in vivo conditions in the mouse liver. DNA damage was also studied. Various oxidative stress parameters and liver histopathology was also evaluated. Melatonin’s anti-kainic acid toxicity could be brought about by counter acting the influence of kainic acid on the levels of the cytokines, immune reactions and free radical production. This work suggests that melatonin receptors present could be mediate the hepatoprotective actions of melatonin therapy.