Loperamide is a safe over-the-counter antidiarrheal drug. However, at supratherapeutic doses, it produces opioid effects. Here, we evaluated the neurotoxic effects of loperamide in rats brain. 20 rats were randomized into 4 groups (A-D) of 5 rats each. Rats in groups A (control) and B received vehicle for 7-day while rats in groups B, C and D were orally gavaged with 1.5, 3 and 6 mg/kg body weight (BW) of loperamide hydrochloride. The results revealed a dose dependent decrease in acetylcholine. Reactive oxygen species increased significantly while antioxidant enzymes were significantly (p < 0.05) lowered in the brain. Loperamide induces necrotic related morphological changes in rat brain with significant increase in malondialdehyde, protein carbonyl and fragmented DNA. Loperamide deplete acetycholine thus causing the accumulation of reactive oxygen species and oxidation of cellular macromolecules. This study provides biochemical evidence supporting the neurotoxicity associated with supra-therapeutic dose consumed for euphoria effect.