Neuroleptics are widely prescribed drugs for the treatment of schizophrenia and related psychiatric disorders. Tardive dyskinesia (TD) is a late complication of prolonged neuroleptic treatment. Despite much research, the pathogenesis of TD remains elusive. It may be caused by loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. Tardive dyskinesia has been associated with cognitive deficits. Reserpine-induced perioral movements (Vacuous chewing movements and tongue protrusions) were recently suggested as a new animal model for tardive dyskinesia. Natural antioxidants were administered for a period of 7 day prior to the reserpine administration and were co-administered along with reserpine for the next 5 days. Repeated treatment with reserpine alone (1 mg/kg) on each other day for a period of five days (1st, 3rd and 5th day) significantly induced perioral movements in rats. Antioxidants like melatonin (2.5 and 5 mg/kg), quercetin (50 and 100 mg/kg) or Withania somnifera (Ws)(100 and 200 mg/kg) significantly reduced the reserpine-induced perioral movements. Memory impairment was assessed by elevated plus maze and passive avoidance paradigms. Reserpine treated rats showed poor performance on elevated plus maze and passive avoidance paradigms indicating memory impairment. Chronic treatment with melatonin, quercetin or WS significantly shortened the TL latency and step down latency on elevated plus maze and passive avoidance paradigms respectively as compared to reserpine alone treated rats. Biochemical analysis revealed that reserpine treatment significantly induced lipid peroxidation and decreased glutathione, superoxide dismutase and catalase levels. Chronic treatment with antioxidants significantly reduced the lipid peroxidation and restored the reserpine-induced decrease in glutathione, SOD and catalase levels. The findings of the present study highlighted the fact that reactive oxygen species and oxidative stress play an important role in the pathophysiology of reserpine-induced perioral movements and memory impairment. Antioxidants could be useful drug candidates for the treatment of reserpine-induced perioral movements and memory impairment.