Because of the threat of resistant <i>Plasmodium sp.</i>, new orally active antimalarials are urgently needed. Inspired by the structure of ellagic acid, exhibiting potent <i>in vivo</i> and <i>in vitro</i> antiplasmodial effects, polyphenolic structures possessing a similar activity-safety profile were synthesized. Indeed, most exhibited a marked <i>in vitro</i> effect (IC<sub>50</sub> < 4 μM) on resistant <i>P. falciparum</i>, without any detrimental effects reported during the toxicity assays (hemolysis, cytotoxicity, <i>in vivo</i>). In addition, they possessed a greater hydrosolubility (from 7 μM to 2.7 mM) compared to ellagic acid. Among them, 30 is the most promising for antimalarial purposes since it displayed a significant parasitaemia reduction after oral administration in mice (50 mg kg<sup>-1</sup>) compared to the orally ineffective ellagic acid. In conclusion, our investigations led to the identification of a promising scaffold, which could bring new insights for malaria treatment.