Aim: This study aimed to assess the neuroprotective effects of metformin compared to selegiline, (each drug alone or in combination) on Parkinson's disease model by reserpine in rats also, it was extended to investigate the mechanisms through which metformin could produce such effect either by its antioxidant effect or genetic recognized by α synuclein and such impact on behavioral changes. Methods: Seven groups were included in the study. The first, second (control and reserpine induced). The third, fourth and fifth were treated with metformin (100, 250 mg/kg), selegiline, (0.25 mg/kg), six and seventh were treated with both selegiline and metformin both doses respectively. Drugs initiated from the first day for 21 days. Morris water maze, hang wire and forced swim tests were done on days 1, 11, 21 to estimate memory changes, motor assessment and depression respectively. Rats were then sacrificed after taking serum samples to assess serum blood glucose; their brains were dissected, homogenized to measure dopamine, α synuclein, malondialdehyde, reduced glutathione levels. Results: reserpine treated group were significant compared to control proving the induction of parkinsonian model which were improved on treatment in all groups with much more improvement in those treated with metformin than selegiline especially those treated by both metformin 100 mg/kg and selegiline. Selegiline treated showed hypoglycemia that was not observed in metformin treated. Conclusion: Metformin on low dose can serve as an add on therapy with selegiline through antioxidant and genetic mechanisms to enhance the neuroprotection in PD patients.