Malaria is a major public health disease affecting millions of people worldwide especially in sub-Saharan Africa, with annual deaths of over 4 million. The emergence of resistant strains of Plasmodium parasite to currently used drugs necessitates the search for newer and affordable cure for malaria from medicinal plants sources. Caesalpinia pulcherrima (L) Sw. is used in traditional medicine for the treatment of various diseases including malaria. Phytochemical, acute toxicity studies and antiplasmodial activities were carried out on the stem bark extracts of the plant. Fraction (HEEA) was fractionated over silica gel column to obtain pure compounds (characterized by IR, UV, 1D and 2D spectroscopy) which were subjected to antiplasmodial investigations. Phytochemical studies revealed the presence of saponins, flavonoids, phenols, terpenoids, tannins, and alkaloids. The LD50 was established at 5656.85 mg/kg body weight in Swiss albino mice. Of all the fractions, HEEA exhibited the highest antiplasmodial activities against both the D6 and W2 Plasmodium falciparum clones at IC50 3.7 and 5.3µg /mL, respectively. Two known compounds; Pulcherrin J (1) and 6β-cinnamoyloxy-7β-hydroxyvouacapen-5α-ol (2) were isolated from HEEA and investigated for antiplasmodial activities. They showed significant inhibition of parasites growth in the D6 and W2 clones with IC50 values 10.25-˃10.62 µM and 10.25-˃10.62 µM, for compound 1 and 2, respectively, as against those of the standard antimalarial drugs (Chloroquine and Artemisinin) with IC50 values <0.0937 and <0.1062, respectively. These findings revealed that C. pulcherrima stem bark possess significant antiplasmodial activities and could be a promising source of newer antiplasmodial agents.