Malaria is a mosquito borne infectious disease caused by a protozoan of the genus Plasmodium. Around 44% of worldâ€Ÿs population is at risk from malaria. Malaria is one of the leading causes of morbidity and mortality in Ethiopia. The most important problem associated with the management of malaria are resistant to or are developing resistance to the most widely available, affordable and safest first line treatments. The study was under taken to evaluate the in vivo antimalarial activity of solvent fractions of the leaves of Vernonia amygdalina against P. berghei infection in mice using four day suppressive test and subsequently body temperature, weight, packed cell volume, parasitemia and mean survival time were determined. The plant has been extracted using cold maceration. 80% methanol crude extract of V. amygdalina was subjected to chloroform, butanol and aqueous fraction. Tween 80 2% and distilled water as negative control and chloroquine 25 mg/kg were used as positive control. Acute oral toxicity test showed that both the aqueous and hydroalcolic extracts and solvent fractions of the leaves of Vernonia amygdalina revealed no mortality and signs of toxicities up to 2000mg/kg. The present study indicated that the percentage suppression of hydroalcoholic extract was 32.47%, 35.4% and 37.67% at 200, 400 and 600mg/kg of the extract, respectively and the percentage suppression of aqueous extract was 21.22%, 22.20% and 24.52% at 200 400 and 600mgmkg of the extract respectively. All doses of crude extracts of V. amygdalina prolonged the survival time, shown prevention against weight loss and prevent PCV reduction in a dose dependent manner. Except aqueous fraction, all doses of chloroform and butanol fractions were suppressed parasitemia significantly. The percentage suppression of chloroform fraction was 21.68%, 23.72% and 33.85 % at 100, 200 andrnXrn400mg/kg of the fraction, respectively. The 100 and 200 mg/kg of butanol fraction resulted in moderate anti-plasmodial activity (18.12%, and 21.03% %, respectively), followed by the 400 mg/kg (26.88%).The mean survival effects of both chloroform and butanol fractions were capable of significantly increasing survival time at all doses compared to negative control. All the tested doses of chloroform and butanol fractions exhibited reduction in rectal temperature of Plasmodium berghei infected mice statistically significant (p