In Cameroon, malaria is still the cause of several deaths yearly and leading to the continued search for new potent leads to fight againstPlasmodium falciparum. Medicinal plants likeHypericum lanceolatumLam. are introduced in local preparations for the treatment of affected people. The bioassay-guided fractionation of the crude extract of the twigs and stem bark ofH. lanceolatumLam. led to the identification of the dichloromethane-soluble fraction as the most active (with 32.6% of the parasiteP. falciparum3D7 survival) which was further purified by successive column chromatography to obtain four compounds identified by their spectrometric data as two xanthones 1,6-dihydroxyxanthone (1) and norathyriol (2) and two triterpenes betulinic acid (3) and ursolic acid (4). In the antiplasmodial assay againstP. falciparum3D7, the triterpenoids3and4displayed the most significant potencies with IC50values of 2.8 ± 0.8μg/mL and 11.8 ± 3.2μg/mL, respectively. Furthermore, both compounds were also the most cytotoxic against P388 cell lines with IC50values of 6.8 ± 2.2μg/mL and 2.5 ± 0.6μg/mL, respectively. Further insights on the inhibition method of the bioactive compounds and their drug-likeness were obtained from their molecular docking and ADMET studies. The results obtained help in identifying additional antiplasmodial agents fromH. lanceolatumand support its use in folk medicine for the treatment of malaria. The plant might be considered as a promising source of new antiplasmodial candidates in new drug discovery.