The study focused on the comparative determination of the effects of the combination of leaf extracts of Carica papaya (CP) and Vernonia amygdalina (VA) and Artemether-based combination therapy (ACTs) on Plasmodium berghei infected male wistar rats. Fifty (50) male wistar rats, weighing 100 to 150g, were allotted into 5 groups (n=7). Group 2 (negative control) was infected but not treated, groups 3-5 which were infected received 250mg/kg b.w each of CP and VA in combination and 4mg/kg b.w of the two reference ACTs. Treatment was done orally once daily for 3 consecutive days, after which the animals were sacrificed and haematological analysis carried out. Afterwards, an observatory period of 7 days commenced after which another round of sacrifice was done. Before treatment, parasitemia count of animals in groups 3-5 was substantially (p<0.05) higher when juxtaposed with group 2. AST and ALT activities were significantly (p<0.05) elevated in group 3-5 when matched with group 2. Plasmodium berghei induction meaningfully (p<0.05) lowered white blood cell (WBC) at all groups. After treatment, the extracts and drug which notably (p<0.05) lowered plasmodium count, RBC, WBC, PCV, Hb and Platelet levels, did not meaningfully(p>0.05) affect the activities of ALP, AST and ALT. After 7 days of observation, the extracts and drug efficaciously (p<0.05) reduced plasmodium count, WBC and ALP activity further at all groups. These results indicate that the leaf extracts in combination are as efficacious as the ACTs.