The present study was designed to evaluate the effect of Plasmodium and Salmonella co-infection in LACA mice. The parasitaemic level, bacterial load, histological alterations and levels of oxidants/antioxidant activity were measured. Co-infected mice had a high parasitaemic level, increased bacterial load, and died earlier than Plasmodium-infected mice. Histologically, co-infected mice had more architectural damage in the liver, spleen, kidney, and brain than the control groups. The level of lipid peroxidation was significantly increased and the activities of antioxidative enzymes (superoxide dismutase and catalase) were decreased in all organs of co-infected mice compared to the control groups, indicating depression of the antioxidant defense system. The present study demonstrates more severe histological and biochemical alterations in co-infected mice, highlighting the importance of early diagnosis for selection of appropriate treatments and reducing the likelihood of further complications.