Continuous emergence of multi-drug-resistant malaria parasites and their rapid spread across the globe warrant urgent search for new anti-malaria chemotherapeutics. Traditional medicinal plants have been the main sources for screening active phytochemicals against malaria. Accordingly, this study was aimed at evaluating in vivo antimalarial activity against chloroquine-sensitive Plasmodium berghei of Osyris quadripartita Salzm. Ex Decne, locally called ‘keret’ in Amharic, which is used for traditional malaria treatment by local people in different parts of Ethiopia. The plant part was collected and identified by a botanist. Crude leaves were extracted using aqueous, methanol and chloroform solvent extracts. Methanol gave the highest yield of the plant extract. Acute toxicity study results indicated that the plant extract did not show any sign of toxicity up to 2000mg/kg. To assess the effect of the plants on the test parasite, a 4-day suppressive standard test was performed. Data were analyzed using paired t-test and analysis of variance (ANOVA). Both aqueous and methanol extract of O. quadripartita significantly (P