Malaria is one of the most important protozoan diseases in the world that cause illness for human.rnResistance to currently available antimalarial drugs remains a major challenge and continued torncause an obstacle in the management of malaria. This calls for development and discovery ofrnnew antimalarial agents from alternative sources such as medicinal plants. As seen from history,rnmost currently used antimalarial drugs were obtained from traditional medicinal plants. Cucumisrnprophetarum is one of the traditional medicinal plants that have been used traditionally in therntreatment of malaria in different parts of Ethiopia. However, it lacks pharmacologicalrninvestigations to confirm its antimalarial activity. Therefore, this study aimed to investigate inrnvivo antimalarial activity of 80ME and solvent fractions of root of C. prophetarum in P. bergheirninfected mice using 4-day suppressive and prophylactic test. Before evaluation of thernantimalarial activity, oral acute toxicity study was carried out. To evaluate the antimalarialrnactivity, three doses of the 80ME and solvent fractions (50mg/kg, 100mg/kg and 200mg/kg)rnwere given to parasite infected mice orally. Parameters including parasitemia level, survival time,rnbody weight, body temperature and packed cell volume were evaluated. In 4-day suppressive test,rnthe chemosuppressive effects exerted by the crude extract, chloroform fraction, butanol fractionrnand aqueous fraction were in a range of 30.84-64.33%, 27.14-48.47%, 24.34-35.39% and 15.9125.82%,rnrespectively. In prophylactic test, the parasite suppression effect exerted by the 80MErnwas in a range of 24.58-39.70%. The highest suppression of parasitemia was displayed by thernmaximum dose (200mg/kg) of 80ME in 4-day suppression test. Furthermore, the 80ME andrnsolvent fractions prevented loss of body weight, body temperature reduction and packed cellrnvolume reduction when compared to the respective negative controls. In addition, they prolongedrnthe survival time of infected mice. In conclusion, the results of this study collectively indicaternthat the root of C. prophetarum has in vivo antimalarial activity which supports the traditionalrnclaim.