Malaria is still one of the most common infectious diseases and leads to various public health problems worldwide. Medicinal plants are promising sources for identifying novel agents with potential antimalarial activity. This study aimed to investigate the antimalarial and the antioxidant activities of Indigofera oblongifolia on Plasmodium chabaudi-induced spleen tissue injury in mice. Mice were divided into five groups. The first group served as a vehicle control; the second, third, fourth, and fifth groups were infected with 1 × 10(6) P. chabaudi-parasitized erythrocytes. Mice of the last three groups were gavaged with 100 μl of I. oblongifolia leave extract (IOLE) at a dose of 100, 200, and 300 mg IOLE/kg, respectively, once daily for 7 days. IOLE was significantly able to lower the percentage of parasitemia. The most effective dose was the 100 mg IOLE/kg, which could reduce the parasitemia from about 38 to 12 %. The infection induced spleen injury. This was evidenced by disorganization of spleen white and red pulps, appearance of hemozoin granules and parasitized erythrocytes. These changes in spleen led to the increased histological score. Also, the infection increased the spleen oxidative damage where the levels of nitrite/nitrate, malondialdehyde, and catalase were significantly altered. All these infection-induced parameters were significantly improved during IOLE treatment. In addition, the mRNA expression of inflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha were upregulated after infection with P. chabaudi, whereas IOLE significantly reduced the expression of these genes. Our results indicate that I. oblongifolia leaves extract exhibits a significant antimalarial and antioxidant effects, and protects host spleen tissue from injuries induced by P. chabaudi.