Individuals afflicted with occupational formaldehyde (FA) exposure often suffer from abnormal behaviors such as aggression, depression, anxiety, sleep disorders, and in particular, cognitive impairments. Coincidentally, clinical patientswithmelatonin (MT) deficiency also complain of cognitive problems associated with the above mental disorders. Whether and how FA affects endogenousMT metabolism and induces cognitive decline need to be elucidated. To mimic occupational FA exposure environment, 16 healthy adultmalemice were exposed to gaseous FA (3mg/m3) for 7 consecutive days. Results showed that FA exposure impaired spatial memory associated with hippocampal neuronal death. Biochemical analysis revealed that FA exposure elicited an intensive oxidative stress by reducing systemic glutathione levels, in particular, decreasing brainMT concentrations. Inversely, intraperitoneal injection ofMTmarkedly attenuated FA-induced hippocampal neuronal death, restored brainMT levels, and reversed memory decline. At tissue levels, injection of FA into the hippocampus distinctly reduced brain MT concentrations. Furthermore, at cellular and molecular levels, we found that FA directly inactivated MT in vitro and in vivo. These findings suggest that MT supplementation contributes to the rescue of cognitive decline, and may alleviate mental disorders in the occupational FA-exposed human populations.