Paraoxon is the bioactive metabolite of organophosphate (OP) pesticide, parathion. This study aimed to evaluate the expression of apoptosis-related genes and histopathological changes in rat prefrontal cortex following exposure to three different doses of paraoxon. Paraoxon (0.3, 0.7, or 1 mg/kg) or corn oil (vehicle) were intraperitoneally injected to adult male Wistar rats. After 14 or 28 days, mRNA and protein levels of Bax, Bcl-2, and caspase-3 were measured in prefrontal cortex using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting, respectively. In addition, neuronal injury and astrocyte activation were assessed using cresyl violet staining and glial fibrillary acidic protein (GFAP) immune-positive cells, respectively. Treatment with 0.7 and 1 mg/kg of paraoxon increased mRNA and protein levels of Bax and caspase-3 at 14 and 28 days post-exposure, while mRNA and protein levels of Bcl-2 decreased only in 1 mg/kg group after 14 days. Furthermore, a significant decrease in the number of neurons and a significant increase in the number of GFAP-positive cells were observed in rats receiving 0.7 and 1 mg/kg of paraoxon at both time points. Collectively, our results showed that apoptosis is a major mechanism for neuronal damage after exposure to paraoxon. Also, paraoxon-induced neuronal loss was correlated with activation of astrocytes. Since paraoxon-induced neuronal damage is closely related to convulsion, clinical management of convulsion could protect neuronal brain damage.