Abstract: Background: Exposure to chlorpyrifos have been shown to induce short term sensorimotor changes in rats, which has been linked to oxidative stress, cypermethrin also induces oxidative stress. This study was therefore aimed at evaluating the ameliorative effects of melatonin on sensorimotor changes induced by co-administration of chlorpyrifos and cypermethrin in male Wistar rats. Materials and Methods: Fifty adult male Wistar rats were divided into five groups of ten rats each. Group I and II were given distilled water and soya oil (2 mL kg–1), respectively. Group III was administered with melatonin at 0.5 mg kg–1 only. Group IV was administered with CPF (8 mg kg–1 to 1/10th LD50) and CYP (30 mg kg–1 to 1/10th LD50) group V was administered with CPF (8 mg kg–1 to 1/10th LD50), CYP (30 mg kg–1 to 1/10th LD50) and 30 min later melatonin (0.5 mg kg–1). The regimens were administered orally by gavage once daily for 12 weeks. Sensorimotor performances were determined at intervals during the study thereafter the brain was evaluated for malonaldehyde and acetylcholinesterase concentrations. Results: There was reduced loco motor activity, decreased grip time, impaired efficiency of locomotion, reduced inclined plane performance, increased brain malondialdehyde concentration and decreased brain acetylcholinesterase concentration in the chlorpyrifos and cypermethrin treated group which were all ameliorated by melatonin pre-treatment. Conclusion: The study showed that treatment with melatonin ameliorated the sensorimotor deficits induced by sub-chronic co-administration of chlorpyrifos and cypermethrin.