Malaria is one of the most serious natural hazards faced by human society. Although plant leaves of Indigofera oblongifolia have been used for the treatment of malaria in Saudi Arabian society, there is no laboratory-based evidence for the effectiveness and safety of the plant. This study therefore was designed to investigate the antimalarial and spleen protective activity of I. oblongifolia leaf extract (IOLE) in mice. Three doses (100, 200 and 300 mg/kg) of IOLE were used to treat mice infected with Plasmodium chabaudi-parasitized erythrocytes. The suppressive effect produced by the 100 mg/kg dose on parasitemia was highly significant compared to the infected nontreated group. This dose was also able to repair the change in the thickness of the mice spleen and significantly lower the number of apoptotic cells in the spleen. Moreover, I. oblongifolia also altered gene expression in the infected spleen. On day 7 postinfection, the mRNA expression of six genes - with immune response functions - was upregulated by more than twofold, while that of 24 other genes was downregulated. Among the differentially up- and downregulated genes under the effect of IOLE, we quantified the expression of Ccl8, Saa3, Cd209a, and Cd209b mRNAs. The expression data, determined by microarrays, were largely consistent with the expression analyses we performed with several arbitrarily selected genes using quantitative polymerase chain reaction (PCR). Based on our results, I. oblongifolia exhibits antimalarial activity and could protect the spleen from P. chabaudi-induced injury.