Introduction: Oxidative stress plays a central role in the pathogenesis of Parkinson’s disease (PD). Several antioxidants have been explored but no study have shown the efficacy or benefits of combining vitamins C and E in ameliorating the motor and cognitive impairments associated with PD and there is no existing therapy that halts or slows the progression of PD yet. Aim: This study was aimed at finding out whether combining vitamins C and E confer protection against reserpine-induced motor and cognitive impairments as well as oxidative stress in mice. Methods: Twenty-five mice were randomly assigned into 5 groups of 5 animals each. Group I received distilled water only. Groups II-V received reserpine 0.1 mg/kg intraperitoneally on alternate days. In addition to reserpine, Group III received vitamin E 200 mg/kg/day orally, group IV received vitamin C 250 mg/kg/day orally and group V received combined vitamin E 200 mg/kg/day and vitamin C 250 mg/kg/day orally. All vitamins were given one hour before reserpine administration for 28 days. Neurobehavioral assessment using novel object recognition test (NORT), Y-maze, beam walk and open field test (OFT) was carried out. Thereafter, the mice were humanely sacrificed and brain homogenate made. Values at P<0.05 were considered significant. Ethical approval was obtained from the Ahmadu Bello University Committee on Animal Use and Care (Approval No.: ABUCAUC/2020/71). Results: The poor discrimination index noted in group II (-0.35±0.23) was significantly ameliorated in group V (0.59±0.12). There was also significant increase in percentage alternation (66.7±9.25%) but decrease in number of foot slips (0.3±0.25) and time taken to reach the safe box (3.00±0.41s) in group V compared to the other groups. In the OFT, the transfer latency was significantly decreased (10.3±1.45s) while the number of lines crossed was increased (56.0±13.53) in group V compared to the other groups. The malondialdehyde concentrations was significantly decreased in all vitamin-treated groups compared to group II (42.2 ± 028 µmol/L). But a significant increase in superoxide dismutase and catalase levels was observed across all the vitamin-treated groups compared to group II. Conclusion: The co-administration of vitamins C and E confers a protective effect against motor and cognitive impairments and oxidative stress induced by reserpine in mice. Key words: co-administration, cognitive impairment, motor impairment, oxidative stress, protective, vitamins.