Malaria is still taking the lead as one of the deadliest infectious diseases worldwide, appealing continuous research for further understanding the biology and the pathogenesis of this fascinating parasite. Discovering effective alternative drugs, however, remains a challenging task to address today’s enigmatic problem, the emergence of resistant strains. Factually, the presence of potent natural products considered as a basis for traditional medicine. Ziziphus spina-christi (L.) is a common plant in gulf region and other nations, as a part of their traditional medicine. The aim of this study was to evaluate the antiplasmodium and the antioxidant activity of Z. spina-christi leaf extracts (ZLE) against Plasmodium berghei induced liver and spleen injury. The study involved three groups; a vehicle control group, infected with 106 P. berghei-parasitized erythrocytes group and ZLE treated-infected mice with 106 P. berghei-parasitized erythrocytes group. The histopathological examination of the liver and spleen showed sever histological changes. Animals treated with ZLE showed a significant improvement in the histological picture of liver and spleen. Biochemical analysis revealed that treatment with ZLE resulted in a significant reinstating of the oxidative markers back to normal level. It could be concluded that ZLE have a power protective role against Plasmodium infection.