The aim of this study is to determine the protection of ethanolic annona muricata (soursop) leaves extract on cyclophosphamide induced toxicity and oxidative stress in liver of male wistar rat. The healthy male albino rats of wistar strain, after acclimatization for a period of two weeks were randomly distributed to three (3) groups with four (4) rats in each group, group 1 served as control and was feed on pelletized growers feed and distilled water for 14 days. Group 2 served as positive control and was feed on pelletized growers feed and distilled water throughout the experiment (14days), then received 100mg/kg per body weight (b.w.) of cyclophosphamide via injection, and were sacrificed after one day. While group 3 served as test and was feed on pelletized growers feed and distilled water, and also 100mg/100kg (b.w.) of ethanolic leaves extract of soursop for 14 days, then received 100mg/kg per body weight (b.w.) of cyclophosphamide via injection, and were sacrificed after one day. For the methodology, hepatic anti-oxidant enzymes, ALT, AST, and histopathology of the liver were the parameters assayed using biochemical methods. The results showed that there was a significant decrease (P˂0.05) in SOD activites of wistar albino rats following the administration of cyclophosphamide. However, treatment of rats with cyclophosphamide was observed to have caused a significant increase in MDA levels. Administration of Annona muricata extract was observed to have reversed the adverse effects caused by cyclophosphamide. The results showed that there was a significant increase (P˂0.05) in the enzyme levels compared to the control in albino male rat liver after the administration of the cyclophosphamide. However, administration of extract was observed to have ameliorated the effects of cyclophosphamide induced damage thereby causing the decrease in ALT and AST concentrations. In conclusion, Annona muricata leaves possess hepatoprotective properties and can therefore be recommended for treatment of hepatotoxicity and oxidative stress.