Rural dwellers in Nigeria and other parts of West Africa use root barks of Zanthoxylum zanthoxyloides L. for treating sickle cell anaemia, cancers, fever and malaria. This study evaluated in vitro anti-plasmodial, and in vivo malaria chemoprotective attributes of methanol extract of Z. zanthoxyloides root bark (ME) and its n-hexane (NHF), ethyl acetate (EAF) and n-butanol (NBF) fractions. The in vitro anti-plasmodial activities against drug-resistant strain (K1) of Plasmodium falciparum and malaria chemoprotective properties against chloroquine-sensitive P. berghei in mice by ME and its fractions were evaluated using standard methods. EAF gave the highest inhibitory activities (IC₅₀ = 2.76 mg/ml) against chloroquine-resistant strain (K1) of P. falciparum, followed by ME (IC₅₀ = 5.54 mg/ml), NBF (IC₅₀ =10.96 mg/ml) and NHF (IC₅₀ = 11.47 mg/ml). Compared to malaria-infected-untreated mice, pre-treatment with 400 mg/kg each of EAF and ME suppressed malaria parasite growth by 92% and 81%, respectively relative to 86% by 28 mg/kg chloroquine phosphate. ME and EAF pre-treatment further prevented malaria associated cytopenia unlike infected-untreated mice. These anti-plasmodial and malaria chemoprotective properties could be attributed to phytochemicals in the herbal drugs whose mechanisms of action should be determined in further studies.