Malaria is one of the most severe public health problems worldwide. Here, we investigated the ameliorative role of berberine against Plasmodium chabaudi-induced spleen injury. Mice were divided into 3 groups. The first group served as a vehicle control, the second group was infected with 103 P. chabaudi infected erythrocytes and the third group was infected with P. chabaudi then treated with 10 mg/kg berberine for 10 days. Berberine was significantly able to lower the percentage of parasitemia. The infection induced splenomegaly and spleen injury. This was evidenced by fused splenic white pulp areas, diffuses appearance of the marginal zones, and increased number of macrophages in the red pulp. These changes in spleen led to the increased histological score. Berberine treatment caused a marked improvement in the splenic architecture and could offer protection against spleen tissue injury. Further studies are required to know the mechanism of berberine action against murine malaria.