Background Aim. In case of high-dose acetaminophen intake, the active metabolite can not bind to the glutathione, thereby inducing cellular necrosis through binding to the cytosol proteins. This trial was performed to histologically and biochemically investigate whether leptin was protective against liver damage induced by paracetamol at toxic doses. Material and Method. In our trial, 30 female rats, divided into 5 groups, were used. IP leptin administration was performed after an hour in the group of rats, in which paracetamol poisoning was induced. The groups were as follows: Group 1: the control group, Group 2: 20 µg/kg leptin, Group 3: 2 g/kg paracetamol, Group 4: 2 g/kg paracetamol + 10 µg/kg leptin, and Group 5: 2 g/kg paracetamol + 20 µg/kg leptin. Results. The most significant increase was observed in the PARA 2 g/kg group, while the best improvement among the treatment groups occurred in the PARA 2 g/kg + LEP 10 µg/kg group (p < 0.05). While the most significant glutathione (GSH) reduction was observed in the PARA 2 g/kg group, the best improvement was in the PARA 2 g/kg + LEP 10 µg/kg group (p < 0.05). Conclusion. Liver damage occurring upon paracetamol poisoning manifests with hepatocyte breakdown occurring as a result of inflammation and oxidative stress. Leptin can prevent this damage thanks to its antioxidant and anti-inflammatory efficacy.