Background <p>The rising prevalence of artemisinin-resistant malaria parasites in Africa underscores the urgent demand for new and effective therapeutic options. Historically, natural products have demonstrated significant anti-<i>Plasmodium</i> efficacy, indicating their potential as a source for malaria drug discovery. Extracts and fractions from <i>Terminalia ivorensis</i> and <i>Terminalia brownii</i> previously exhibited promising anti-<i>Plasmodium</i> potency; however, a thorough assessment of their pharmacodynamics across all asexual blood stages of <i>Plasmodium falciparum</i> and elucidation of their mode of action remains to be conducted. Products from the active fractions of <i>T. ivorensis</i> (Ti^WEa) and <i>T. brownii</i> (Tb^MMeOH:Ea) were investigated throughout the asexual-blood and sexual stages of <i>P. falciparum</i>, focusing on their mechanism of inhibition and interaction with some key targets of haemoglobin metabolism.</p> Methods <p>Both active fractions (Ti^WEa and Tb^MMeOH:Ea) were fractionated by column chromatography, and the chemical structures of the isolated compound were elucidated through physical and spectroscopic techniques. The resulting compound and subfractions were screened in vitro against <i>P. falciparum</i> strains (Dd2, 3D7, and Dd2-GNF156), stage V gametocytes, and mammalian cells. The pharmacodynamics (stage-specific analysis and killing kinetics) of potent inhibitors were assessed and complemented by the effect on haemozoin formation. The molecular interaction between the potent compound and the two target enzymes was investigated through molecular docking.</p> Results <p>The fractionation of Ti^WEa yielded five subfractions (Ti01, Ti02, Ti03, Ti04, Ti05), while Tb^MMeOH:Ea yielded three subfractions (Tb01, Tb02, Tb03) along with one compound (01) characterized as eschweilenol C. All Subfractions demonstrated good activity on susceptible and multidrug-resistant strains of <i>P. falciparum</i> (3D7 and Dd2) with an IC₅₀ ranging from 0.15 to 5.73&#xa0;µg/ml. eschweilenol C equally displayed an IC₅₀ of 490.74 and 379.20&#xa0;nM, respectively, on <i>Pf</i>Dd2 and <i>Pf</i>3D7. Two top hits subfractions (Ti03; Ti04) from Ti^WEa and eschweilenol C from TbMMeOH:Ea exhibited a perfect antiplasmodial profile (IC₅₀ &lt; 1&#xa0;µg/ml); good selectivity (SI &gt; 10) and demonstrated no spontaneous loss of efficacy when tested against mutant resistant strain (<i>Pf</i>Dd2-GNF156) of <i>P. falciparum</i>. Ti03, Ti04, and eschweilenol C reduced haemozoin production, exhibited killing activity on ring and trophozoite stages and showed significant binding affinity to <i>Pf</i>M1AAP and <i>Pf</i>M17LAP.</p> Conclusion <p>This study identifies eschweilenol C as a promising candidate for malaria drug discovery efforts and its significance for further exploration in the context of the emergence of artemisinin-resistant parasites in Africa.</p>