This study was designed to examine the protective effects of N-acetyl cysteine (NAC) and erdosteine (ERD) on hippocampal tissue damage associated with paracetamol (acetaminophen) intoxication. Thirty female Wistar Albino rats were divided randomly into six equal groups: control; paracetamol (1 g/kg); paracetamol (1 g/kg) + ERD (150 mg/kg/day); paracetamol (1 g/kg) + NAC (140 mg/kg bolus, followed by 70 mg/kg); NAC control (140 mg/kg bolus, followed by 70 mg/kg) and ERD control (150 mg/kg/day), given orally in this study. In all the experimental groups, the protective effects of NAC and ERD were investigated by analysis of histopathology measurement on hippocampal tissues. Histopathological examination was described by neuronal degeneration, edema, and vascular congestion. Neuronal degeneration (p<0.01), edema (p<0.00) and vascular congestion (p=0.006) were increased by significant in paracetamol experiment group, when compared with EDR and NAC treatment groups. The use of ERD and NAC was significantly decreased the severity of histopathological changes, such as neuronal degeneration, edema and vascular congestion, after experimentally paracetamol-induced intoxicity in rat hippocampal tissues. Also, the results of this study have been indicated that NAC is more protective against paracetamol intoxicity than ERD in the tissues.