Chrozophora senegalensis is traditionally used to treat malaria. The plant extracts were prepared by cold maceration with 4 different solvents n-hexane, ethyl ether, methanol, and aqueous. Phytochemical analysis shows the presence of tannins, alkaloids, saponins, flavonoids and phenolic in the methanol and aqueous extracts while the ethyl ether and n-hexane extracts contains terpenes, tannins and phenolics. Ethylether has flavonoids and n-hexane has traces of alkaloids.The extracts were tested in vitro against cultured Plasmodium falciparum. The highest inhibition of the P. falciparum with an IC50 of 2.37µg/ml` was demonstrated by the methanol extract followed by aqueous extract with IC50 of 13.36µg/ml, ethylether 32.47µg/ml and least by n hexane 37.68µg/ml. Further investigation against malarial cysteine protease with the four extracts shows highest inhibitory activity of the enzyme in the methanol extract with percentage inhibition of 80% and also 76%, 29%, and 15% for aqueous, n- hexane and ethyl ether respectively. Quantitative phytochemical screening of the methanol extract shows that tannins content was highest with 3.12mg/100g followed byalkaloids 3.10mg/100g, flavonoids 2.51mg/100g, phenolics 2.24mg/100g, saponins 1.69mg/100g and then terpenes 1.61mg/100g. Fractionation of the most active extract that is the methanol extract gave rise to 50 fractions which were pooled to ten different fractions according to their similarities in Rf values. The ten fractions were also further tested against the enzyme malarial cysteine protease. Fraction 3 showed highest inhibitory activity. Characterization of fraction three that shows the best inhibitory activity through gas chromatography/mass spectroscopy revealed the presence of nitro-benzoic acid and ellagic acid alone side other fatty-acids and their derivatives. The anti- plasmodial effect of the methanol extract of the plant could be due to its cysteine protease inhibitory activity. Further work on fraction 3 will be required to characterized and isolate the active compound.