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Ethnopharmacological Relevance: Plasmodium resistance to antimalarial drugs raises the urgent need to seek for alternative treatments. Aqueous extract of Hibiscus asper leaves is currently used in malaria management but remains less documented., Aim of the Study: The study aims to evaluate antimalarial effects of the aqueous extract of Hibiscus asper. UHPLC/MS, was used to identify some likely compounds present in the plant that were thereafter docked to some malaria parasite proteins., Study Design: In vitro anti-plasmodium and antioxidant, UHPLC/Ms analysis, in vivo antimalarial of the plant extract, and in silico molecular docking prediction of some identified compounds were performed to investigate the pharmacological effects of H. asper., Material and Methods: The in vitro antiplasmodial activity of the extract was carried out on Plasmodium falciparum strains using SYBR-green dye; then, the curative antimalarial activity was conducted on Plasmodium berghei NK65-infected male Wistar rats. The UHPLC/MS analysis was used to identify plant compounds, followed by interactions (docking affinity) between some compounds and parasitic enzymes such as P. falciparum purine nucleoside phosphorylase (2BSX) and 6-phosphogluconate dehydrogenase (6FQY) to explore potential mechanisms of action at the molecular level., Results: No hemolysis effect of the extract was observed at concentrations up to 100 mg/mL. In vitro test of the aqueous leaves extract of H. asper showed inhibitory activity against P. falciparum Dd2 and 3D7 strains with IC 50 values of 19.75 and 21.97 μg/mL, respectively. The curative antimalarial test of the H. asper extract in infected rats exhibited significant inhibition of the parasite growth (p < 0.001) with inhibition percentage of 95.11%, 97.68% and 95.59% at all the doses (50, 100 and 200 mg/kg) respectively. The extract corrected major physiological alterations such as liver and kidney impairments, oxidative stress and architectural disorganization in liver, spleen and kidneys tissues. The UHPLC/MS analysis identified 7 compounds, namely chlorogenic acid, azulene, quercetin, rhodine, 1-ethyl-2,4-dimethyl benzene and phthalan. Out of seven compounds identified in the extract quercetin and phthalan showed higher in silico inhibitory activity against P. falciparum purine nucleoside phosphorylase and Plasmodium falciparum 6-phosphosgluconate dehydrogenase parasite enzymes., Conclusion: These findings indicate that H. asper could be a promising complementary medicine to manage malaria. Meanwhile, the affinity of annoted compounds with these enzymes should be further confirmed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)