Introduction: The development of parasite resistance to first-line antimalarial medicines, especially the ACTs, has made the research and development of novel antimalarial medications vital. Globimetula oreophila, a plant used in traditional medicine to treat malaria, is an example of a natural product that may provide new antimalarial drugs with fewer side effects, less drug resistance, and greater efficacy than synthetic drugs. This study aims to evaluate the antiplasmodial properties of G. oreophila's fractions. Method: After collection and authentication, the leaves were air-dried and reduced in size using a pestle and mortar. The pulverized plant was macerated in 70% ethanol and fractionated with solvents in the increasing polarity of n-hexane, chloroform, ethyl acetate, and n-butanol to produce the various fractions. The antiplasmodial activity of the n-hexane, chloroform, ethyl acetate, and n-butanol fractions of Globimetula oreophila leaf extract was assessed using an in vivo method in Plasmodium berghei-infected mice. Results: In the mice, the fractions' median fatal dose (LD₅₀) was calculated to be more than 5000 mg/kg. At doses of 125, 250, and 500 mg/kg, the fractions significantly (p<0.001) reduced the parasitemia level. Conclusion: The fractions of G. oreophila showed significant in vivo antiplasmodial activity, which upholds the earlier in vivo findings for the crude extract as well as its folkloric use.