The aim of this study was designed to evaluate the possible protective effects of thymoquinone (TQ) on the neuronal injury in the frontal cortex after chronic toluene exposure in rats. The rats were randomly allotted into one of three experimental groups: A (control), B (toluene treated) and C (toluene treated with TQ); each group contain 10 animals. Control group received 1ml normal saline solution and toluene treatment was performed by inhalation of 3,000 ppm toluene, in a 8 h/day and 6 day/week order for 12 weeks. The rats in TQ treated group was given TQ (50 mg/kg body weight) once a day orally for 12 weeks starting just after toluene exposure. Tissue samples were obtained for histopathological investigation. To date, no histopathological changes of neurodegeneration in the frontal cortex after chronic toluene exposure in rats by TQ treatment have been reported. In this study, the morphology of neurons in the TQ treatment group was well protected. Chronic toluene exposure caused severe degenerative changes, shrunken cytoplasma, severely dilated cisternae of endoplasmic reticulum, markedly swollen mitochondria with degenerated cristae and nuclear membrane breakdown with chromatin disorganization in neurons of the frontal cortex. We conclude that TQ therapy causes morphologic improvement on neurodegeneration in frontal cortex after chronic toluene exposure in rats. We believe that further preclinical research into the utility of TQ may indicate its usefulness as a potential treatment on neurodegeneration after chronic toluene exposure in rats.