Formaldehyde (FA) is an organic chemical which is widely used all over the world and has hazardous effects for the environment. FA can react with many biomolecules in the biological systems and lead to toxic effects on humans. Melatonin (MEL), a neurohormone produced by pineal gland, has been shown to be an effective antioxidant with free radical scavenging properties. The present study aimed to evaluate the ameliorative effects of MEL on FA-induced toxicity by monitoring oxidant/antioxidant and histopathological changes in the lung, liver and kidney tissues of rats as well as DNA damage in the blood samples. FA was administered through inhalation at a rate of 6 ppm for 6 weeks and intraperitoneal injection at a rate of 10 mg/kg/day for 14 days. MEL was administered in related groups at a rate of 10 mg/kg/day. Upon the completion of the experimental protocol, tissues were dissected for processing biochemical assays and routine histological staining. Blood samples were collected to investigate DNA damage with the comet assay and ELISA kit for 8-hydroxydeoxyguanosine (8-OHdG). FA exposures increased the levels of DNA damage, malondialdehyde and myeloperoxidase activity and reduced glutathione levels. FA also significantly raised the level of tissue reactive oxygen species. FA-induced morphological changes in the tissues were also observed with the light microscope. These alterations were reversed by MEL treatment. In conclusion, the present study suggests that oxidative mechanisms play an important role in FA toxicity. MEL ameliorates oxidative tissue and DNA damage resulting from FA-induced toxicity by balancing oxidant-antioxidant status, inhibiting neutrophil infiltration and reducing 8-OHdG level, and might be beneficial in reducing FA-induced oxidative tissue and DNA damage.