en <p style="text-align:justify"><span style="font-size:11pt"><strong><span style="font-size:10.0pt">Background:</span></strong><span style="font-size:10.0pt"> Resistance to antimalarial medications, particularly in <em>Plasmodium falciparum </em>(<em>P. falciparum</em>), has emerged as a significant challenge, highlighting the need for innovative therapeutic strategies. Green-synthesized magnesium oxide nanoparticles (MgO NPs) represent a promising approach to therapeutic interventions. This study presents one of the first detailed evaluations of green-synthesized MgO NPs derived from <em>Achillea millefolium</em> (<em>A. millefolium</em>) against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) <em>P. falciparum</em> strains.</span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><strong><span style="font-size:10.0pt">Methods:</span></strong><span style="font-size:10.0pt"> In this study, MgO NPs were biosynthesized using <em>A. millefolium</em> extracts with varying solvent ratios. The nanoparticles were characterized using UV-Vis, FTIR, FESEM, and DLS techniques. Cytotoxicity was assessed <em>via</em> MTT and hemolysis assays. Their antiplasmodial efficacy was evaluated <em>in vitro</em> against chloroquine-sensitive (3D7) and -resistant (K1) <em>P. falciparum</em> strains.</span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><strong><span style="font-size:10.0pt">Results:</span></strong><span style="font-size:10.0pt"> The synthesized MgO NPs displayed quasi-spherical morphology and nanoscale size. Among tested formulations, the most effective showed IC₅₀ values of 0.17 <em>mg/ml</em> for the 3D7 strain and 0.76 <em>mg/ml</em> for the K1 strain, indicating significant antiplasmodial activity.</span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><strong><span style="font-size:10.0pt">Conclusion: </span></strong><span style="font-size:10.0pt">Green-synthesized MgO NPs using <em>A. millefolium</em> demonstrated potent antiplasmodial activity at low IC₅₀ concentrations, showing efficacy against both chloroquine-sensitive and -resistant <em>P. falciparum</em> strains. These findings highlight their promise as plant-based nanotherapeutics for malaria treatment.</span></span></p> Achillea millefolium, Antimalarials, Chloroquine, Magnesium oxid, Malaria, Plasmodium falciparum 249 257 https://www.ajmb.org/En/Article.aspx?id=70626 https://www.ajmb.org/PDF/En/FullText/70626.pdf NiloufarKhamsehpourDepartment of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran92400HalehHanifianDepartment of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran92401MehdiNateghpourResearch Center for Quran, Hadith and Medicine, Tehran University of Medical Sciences, Tehran, Iran92402AhmadRaeisi92403MohammadShabaniDepartment of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran92404AramKhezriDepartment of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran92406Seyed AhmadDehdastCenter for Research Endemic Parasites of Iran, Tehran University of Medical Sciences, Tehran, Iran92407LeilaFarivarDepartment of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran92408SaeedShahsavariDepartment of Biostatistics and Epidemiology, School of Health, Alborz University of Medical Sciences, Karaj, Iran92409GholamrezaHassanpour92435