Malaria remains a global health crisis, primarily driven by drug-resistant Plasmodium falciparum strains, necessitating the urgent discovery of novel and safe antimalarial agents. The aim of this study was to identify potent inhibitors against four essential P. falciparum enzymes: PfCullin-2, PfNADP-IDH, PfPKG, and PfAMA1. This study employed a structure-based in silico approach, combining molecular docking, drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses, to screen phytochemicals from Dioclea reflexa. Molecular docking results identified three potent lead compounds with high binding affinities (ΔG) often surpassing or equaling standard antimalarial drugs. The most potent hit was the phytosterol β-Sitosterol which showed a maximum affinity of −10.7 kcal/mol against PfCullin-2, exceeding the affinity of the control drug Atovaquone (−10.4 kcal/mol). Moreover, Lupeol (triterpenoid) was a dual inhibitor, demonstrating significantly superior binding to PfNADP-IDH (−9.6 kcal/mol) and PfAMA1 (−8.4 kcal/mol) compared to Primaquine (−5.7 and −6.6 kcal/mol, respectively). The flavonoid 7,4'-Dihydroxyflavone exhibited a docking score of −8.9 kcal/mol against PfPKG, comparable to the reference drug Artemisinin (−9.2 kcal/mol). Pharmacokinetic evaluation revealed a trade-off between potency and drug-likeness. While β-Sitosterol and Lupeol are the most potent binders against the malaria target receptors, their high lipophilicity resulted in one Lipinski violation and predicted poor aqueous solubility. In contrast, 7,4'-Dihydroxyflavone showed zero Lipinski violations and good solubility, establishing it as the most drug-like candidate. Toxicity screening predicted all three compounds to be inactive for major risks including hepatotoxicity, mutagenicity, and carcinogenicity. However, β-Sitosterol and Lupeol were flagged for neurotoxicity, while 7,4'-Dihydroxyflavone was flagged for nephrotoxicity.