Magister Pharmaceuticae - MPharm / Malaria disease poses substantial health risks to many nations, especially in Africa, where it primarily affects pregnant women, children, and immunocompromised patients. However, current antimalarial drugs have limitations such as low safety profile and particularly widespread treatment failure due to the increasing resistance of Plasmodium falciparum, the major causative organism to artemisinin-based therapy (ACT) and other chemotherapeutics. In the light of this, there is a pressing need for new antimalarial drugs with novel mechanisms of action and satisfactory pharmacokinetic properties, which has led to the current study. Furthermore, current antimalarial drugs target specific stages of the Plasmodium life cycle. For instance, chloroquine targets the erythrocytic stage while primaquine targets the liver stage. However, these therapies cannot achieve complete elimination of the parasite once the life cycle has been established in the body. Hence, the goal of this study is to combat resistance by finding novel compounds that can bind to a multiple-staged protein in Plasmodium falciparum. Based on this consideration, falstatin was chosen as the protein target for this study because it was observed to play a crucial role in the degradation of haemoglobin, rupture of erythrocytes by mature schizonts, and subsequent invasion of erythrocytes by free merozoites. Hence, the protein, falstatin can be targeted to inhibit cell growth and cause plasmodial cell death in merozoites as well as schizonts of Plasmodium falciparum. Therefore, it is intended that compounds that bind to falstatin could serve as novel antimalarials that target multiple stages of the Plasmodium life cycle. Consequently, this study explored the structure-based virtual screening approach to identify compounds that could bind to the protein target, falstatin in Plasmodium falciparum. An extensive literature review identified falstatin as the multi-staged drug target for this study, while homology modelling was used to generate the three-dimensional structure of falstatin. Molecular docking was conducted to predict the binding energy of compiled antiplasmodial compounds to falstatin while druglikeness analysis was used to prioritize compounds according to their ADMET (absorption, distribution, metabolism, excretion and toxicity) properties. The top-ranked compound, based on a novel ligand scoring function, was then subjected to molecular dynamics (MD). Following this step, rescoring analysis was performed on the top 5 compounds using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring function to gain insight into their component binding energies. Thereafter, a pharmacophore hypothesis was developed based on the 5 top-ranking compounds in order to screen other compound libraries in the future. From the results, TCMDC 131646, TCMDC-124274, TCMDC-138266, TCMDC 123844 and TCMDC 131234 possessed good binding energies and satisfactory ADMET properties showing high ligand scores of 77.1, 75.4, 75.4, 75.4 and 73.1 respectively (on a total scale of 100). Also, the study revealed that the top-ranked compound, TCMDC 131646 had a binding energy of -6.15 KJ/mol, contained no toxicophore and conformed to Lipinski, Egan and Muegge rules of druglikeness. Findings from the MD simulation demonstrated that TCMDC 131646 strongly interacted with the protein, falstatin. Morealso, the study revealed that TCMDC 131646 is structurally diverse from chloroquine, artemisinin, artemether and lumefantrine, indicating that it may possess a distinct mechanism of action. The rescoring analysis of TCMDC-131646, TCMDC 124274, TCMDC-138266, TCMDC 123844 and TCMDC 131234 predicted negative binding energies ≤ -4.662 KJ/mol for the top compounds, further indicating that these compounds are likely to bind strongly with falstatin. Additionally, the developed pharmacophore hypothesis contained -H-N-C=O and N-H moieties which strongly suggested that the presence of electron-withdrawing groups could be vital for the inhibition of falstatin at the active site. Overall, TCMDC 131646 was predicted to be a drug-like and safe compound that could inhibit falstatin in Plasmodium falciparum. Chemical-disease co-occurrence analysis in literature revealed that this compound showed in-vitro antiplasmodial activity at an IC50 of 0.226μM and has also shown in vitro activity for neuralgia, hyperalgesia and arthritis. The research recommends TCMDC 131646 as a potential antimalarial hit compound that could yield novel analogues by hit expansion. However, confirmatory in-vitro and in-vivo studies are required to substantiate these predictions