Background. Emergence of drug resistance and lack of therapeutic efficacy of modern antimalarial drugs are the most triggering factors for the searching of new lead compounds with different mechanisms of action. Medicinal plants with documented traditional uses are a viable option for treatment of malaria. Traditionally, the leaf latex of Aloe weloensis has been used in the treatment of malaria in Ethiopia. Hence, this study was undertaken to investigate the antimalarial activity of the leaf latex of Aloe weloensis in Plasmodium berghei-infected mice. Methods. A four-day suppressive test was employed to evaluate the antimalarial effect of the leaf latex of the plant against P. berghei in Swiss albino mice. Mice were randomly assigned in five groups of five animals in each and given 100, 200, and 400 mg/kg of the leaf latex, chloroquine 25 mg/kg, and distilled water. The level of parasitemia, packed cell volume, survival time, temperature, and body weight was used to determine the antimalarial activity. Results. The acute toxicity study indicated that the leaf latex of A. weloensis caused neither mortality nor signs and symptoms of toxicity at a dose of 2000 mg/kg. Furthermore, the 4-day suppressive test indicated that the latex of the plant exhibited a significant parasitemia reduction in a dose-dependent manner as compared to negative control. The leaf latex of the plant exhibited a percent inhibition of 13.05%, 41.87%, and 66.84% at doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg, respectively. The chemosuppression of the antimalarial activity was statistically significant at 100 mg/kg (p<0.05), 200 mg/kg (p<0.01), and 400 mg/kg (p<0.01) as compared to negative control. All doses of the leaf latex prevented weight loss and reduction in temperature and packed cell volume and increased the survival time of infected mice. Conclusion. The results of this study demonstrated that the leaf latex of Aloe weloensis possessed antiplasmodial activity confirming the genuine traditional use of the plant as an antimalarial agent.