In Parkinson's disease models, Rotenone, a popular pesticide and mitochondrial complex I inhibitor, causes dopaminergic neuron loss (PD). Nonetheless, the rotenone neurotoxicity mechanisms are still poorly defined. In this study, we used rotenone to induce Parkinson's disease and investigate its effect on medial prefrontal cortex (mPFC). Thirty rats were divided into two groups (control and Rotenone (n=15) each).Rats in rotenone group received a daily dose of2 mg/kg of rotenone dissolved in 1ml of sun flower oil by subcutaneous injection for 5 weeks. Rotenone group showed bothmotor dysfunction as evaluated byrotaroad (RRT)and open field tests (OFT)and non- motor changes (depression) as evaluated by forced swimming test (FST). Histologically,the rotenone group has shown layer I widening and layer II and layer IIII condensation with marked apoptotic changes and neuropil showed decrease distribution and absence of nerve fibers compared to control group in the mPFC.Immunohistochemically,rotenone groupshoweda depletion of dopaminergic cells in the midbrain (MB)and dopaminergic nerve fibers inthemPFC and aggregation of Lewy bodies (LB) in both tissue together these changes were associatedwith significant increase in the optical density (OD) of caspase- 3 immune expression and significant decrease of OD of GFAP immune expression in the rotenone group compared with control group.Also, rotenone group demonstratedsignificant increase in the lipid peroxidation and nitric oxide as well as significant reduction in the glutathione level in the MB and mPFC comparedwith control group. In conclusion rotenone induced PD model in rats caused behavioral, neurochemical, histological, and immunohistochemical changes in the mPFC.