Resistance of malaria parasite to conventional drugs and the high cost of potent ones have necessitated the search for new drugs. Methyl gallate and palmatine are compounds with known in vitro activities against multidrug-resistant strains of Plasmodium falciparum, but without in vivo activities, which are associated with plants from which they have been isolated. This, therefore, necessitates the evaluation of antimalarial activities of combination of isolated compounds. Thus, the objectives of this study were to evaluate: (i) in vitro antimalarial activity of methyl gallate and palmatine combination (MGPAL); (ii) interaction of methyl gallate and palmatine with selected P. falciparum proteins in silico; (iii) antimalarial activity of MGPAL in P. berghei-infected mice; (iv) antimalarial activity of MGPAL when co-administered with a bio-enhancer in P. berghei-infected mice; (v) antioxidant activities of MGPAL in vitro and in P. berghei-infected mice when co-administered with a bio-enhancer; and (vi) in vivo toxicity of MGPAL when co-administered with a bio-enhancer using selected organ function indices.rnIn vitro antimalarial activity of methyl gallate and palmatine combination was determined using inhibition of Î²-hematin formation assay. Suppressive and curative antimalarial activities of the individual drugs and their combination, with or without piperine (bio-enhancer), were evaluated using P. berghei NK65-infected mice. Antioxidant activities of MGPAL in vitro and in P. berghei-infected mice when co-administered with piperine were evaluated. Toxicological effects of MGPAL when co-administered with piperine were also evaluated in rats. Data were analyzed using Analysis of Variance at P<0.05.rnrnThe findings of this study were that:rni. MGPAL inhibited Î²-hematin formation in vitro (IC50 - 0.73 Âµg/mL, indicating antimalarial activity), with the compounds exhibiting synergistic interaction when combined in ratio 3:2;rnii. Methyl gallate and palmatine exhibited higher affinity for plasmepsins I, II and III than for other proteins studied in silico;rniii. MGPAL in ratio 3:2 (MGPAL3:2), in the absence of piperine, exhibited no in vivo antimalarial activity, causing less than 30% reduction in parasitemia;rniv. MGPAL3:2, in the presence of piperine, caused more than 30% reduction in parasitemia (especially at 12.5 and 25 mg/kg body weight in the suppressive and curative antimalarial tests) in P. berghei NK65-infected mice mainly on days 6 and 8 post-inoculation;rnv. MGPAL3:2 demonstrated DPPH, nitric oxide, hydroxyl radical scavenging activities and induced antioxidant defense system in murine malaria model in the presence of piperine; andrnvi. MGPAL3:2, in the presence of piperine, significantly increased (p<0.05) plasma conjugated bilirubin concentration (at the highest dose), HDL-cholesterol concentration (at doses higher than 12.5 mg/kg body weight) and liver aspartate aminotransferase activity (at doses higher than 25 mg/kg body weight) but significantly reduced (p<0.05) atherogenic index and Low density lipoprotein-cholesterol concentration (at doses higher than 6.25 mg/kg body weight) and plasma Ca2+ concentration (at the highest dose) compared to controls.rnrnThe study concluded that, in the presence of piperine, MGPAL3:2 exhibited antimalarial activity, ameliorated ROS-mediated secondary complications of malaria and adversely affected some liver and kidney functions, especially at higher doses. Further studies on the mechanisms of action of the compound combination should be carried out.