tBackground: Trypanosomiasis is a neglected tropical disease, transmitted by blood-sucking insects andcan affect humans and animals, depending on the species of Trypanosoma parasite. Trypanosoma hasacquired resistance to the majority of drugs used; hence, alternative medicines are required. Indigoferaoblongifolia leaf extract (IOE) has been shown to treat blood stage malaria. Here, IOE was used to demon-strate its effect on Trypanosoma evansi-infected mice.Methods: Analysis of IOE by gas chromatography–mass spectrometry showed the presence of many activecomponents like flavonoids and phenolics. The mice were divided into three groups as follows: vehiclecontrol, T. evansi-infected mice and T. evansi-infected-treated mice.Results: The findings demonstrate a significant effect of IOE treatment on T. evansi-infected mice. Para-sitemia was decreased by 70%, weight loss was reduced, and splenomegaly was significantly decreased.Additionally, IOE improved the histological architecture of the spleen, as shown by the improved histolog-ical injury score post-treatment. Anemia was apparent during the course of infection in T. evansi-infectedmice; this was reversed upon treatment with IOE to almost the normal level of hemoglobin and ery-throcytes. Reduced glutathione and catalase were also ameliorated upon IOE treatment compared to T.evansi-infected mice.Conclusion: Overall, this study shows the ameliorative role of IOE against T. evansi-induced spleen injuryin mice.