Malaria incidences has been a public health concern and it has increased in recent years because of resistance of the malaria parasite to available antimalarial drugs. This research explored the anti-plasmodial effect of the Cissus populnea matrixed in artemether-lumefantrine against Plasmodium berghei infected mice. The matrixed drug was evaluated for prophylactic, curative, and suppressive effect in Plasmodium berghei mice. The swiss Albino mice were grouped into 4 and were inoculated with Plasmodium berghei intraperitoneally except the naïve group. The matrixed drug significantly inhibited parasitemia in prophylactic, curative, and suppressive infections (p<0.05) (45.75%, 37.75, and 60.99%, respectively). However, a significant decrease in PCV, Hb, RBC and increased total and differential white blood cell count was observed in the mice that were treated with the matrixed tablet formulation for prophylaxis and suppression, but no significant hematological effect was observed in the groups that received the matrixed tablet for curative effect. The histopathological analysis of the matrixed drug on different organs showed no observable damage in any of the organs This study suggests that incorporation of Cissus populnea gum in artemether-lumefantrine based tablets possessed promising antimalarial potential with minimal histological and hematological effects.