Background: Malaria is an infectious disease-causing mortality and morbidity in children and adults. Our study planned to measure the antimalarial activity of Combretum molle extract in vivo assays against Plasmodium berghei in Swiss albino mice. Methods: Plasmodium berghei was inoculated to healthy mice and methanolic crude extract and solvent fractions of C. molle at 100, 200, and 400mg/kg/day were administered. Percent parasitemia inhibition, percent change in weight, temperature, packed cell volume, and mean survival time were determined. Data were analyzed using one-way ANOVA followed by the post hoc Tukey HSD test with SPSS software version 24.0 and P < 0.05 considered as statistically significant. Results: Chemosuppresive effect exerted by the methanolic crude extract ranged between 27 and 68%, chloroform fraction 52.93-67.73%, hexane fraction 23.61-44.97%, and aqueous fraction 29.48-51.13%. The curative effect of the crude extract was within the range of 25-49%, chloroform fraction 42.78-69.22%, and prophylactic effect of the crude extract was within the range of 51-76.2%% and chloroform fraction 46.57-71.96%. The utmost effect in all tests on chemosuppresive, curative, prophylactic, prevention of weight loss, temperature and packed cell volume, and an increase in mean survival time was observed at higher doses of the crude extract. Conclusion: From this study, it will be concluded that crude extract of C. molle leaves has been shown promising antimalarial activity. The findings of this study may support the normal use of leaf as a part of the plant for malaria treatment.