Plasmodium knowlesi infections can progress rapidly to life-threatening complications, such as acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), which are driven by the ability of the zoonotic parasite to rapidly replicate towards high parasitemia and the cytoadherence properties of the infected erythrocytes (IRBCs). This study evaluated the anti-parasitic and vasoprotective potential of Annona muricata (soursop) leaf ethanol extract against P. knowlesi. In vitro assays using the P. knowlesi A1-H.1 reference strain revealed significant blood stage schizogony inhibition (IC₅₀: 9.65 µg/mL), specifically targeting the trophozoites. The anti-parasitic activity was concentrated in the <30 kDa subfraction of the extract. Washout assays confirmed that the effect was parasitostatic rather than parasiticidal, where the malaria parasites underwent developmental arrest but remained morphologically normal and resumed growth post-removal. Furthermore, priming human endothelial cell lines with the extract significantly reduced IRBC–endothelial binding. These results demonstrate that A. muricata extract exerts a dual-action effect by arresting P. knowlesi asexual replication and inhibiting IRBC–endothelial cytoadherence. While clinical translation would require exhaustive standardization and chemotypic profiling due to the natural variability of plant compositions, these findings provide a foundational academic framework for the potential of A. muricata leaf extract in mitigating severe knowlesi malaria complications.