We investigated the histomorphological effects of Nauclea latifolia and Coartem® on the antioxidant levels and hippocampus in Plasmodium berghei ANKA infected mice. Forty‐two mice, 6 per group, between 6‐8weeks, of 22‐24 g, were infected and 5 days p.i., treated for 5 days; Group 1 served 10 ml/kg of (0.9% NaCl). Groups 2 and 3 received 500 and 1000 mg/kg of the extract, groups 4, 5 and 6 received n‐hexane, chloroform and butanol fractions at 1000 mg/kg, group 7 received Coartem® ‐ artemether/lumefantrine 5 mg/kg. Parameters evaluated were parasitemia, organosomatic index, superoxide dismutase, catalase, lipid peroxidation, protein, H&E and GFAP staining. Results showed no significant changes in final body weight and organosomatic index in treated groups compared with control, except in group 5 which was increased (p<0.05) compared to the control, there was significantly (p<0.05) decreased parasitemia in treated groups compared to control, with highest % chemosuppression in Coartem® group. Antioxidant and protein levels were not significantly changed (p>0.05) in the treated groups compared to control, except in group 5 which had significantly reduced Catalase. Hippocampal sections showed mild to severe morphological changes with neuronal loss, patechial hemorrhage, neuronal shrinkage, hydropic vacuolations, neuronal polymorphism, and pyknosis. Reactive astrogliosis showed moderate to severe neuroinflammation in treated groups compared to control, except in Coartem group® which may be associated with JAK2‐STAT3 activated signaling pathway in astrocytes, GFAP up regulation, and inositol 1,4,5‐trisphosphate (IP3)‐dependent Ca2+ signaling in astrocytes. In conclusion, curative therapy with ethanolic leaf extract of Nauclea latifolia and Coartem® against Plasmodium berghei ANKA infection in mice, significantly reduced parasitemia, the ethanolic extract did not reverse the parasite induced astrogliosis, which may influence neuronal survival and death, but neuronal shrinking, neuronal loss and pyknosis were mild to severe and this was dose/fraction dependent, however Artemisinin‐combination therapy phenotypically reduced reactive astrogliosis in the hippocampus, but had numerous hydropic vacuolations. The result may validate the use of Coartem® in severe malaria or cerebral malaria.