To investigate the mechanism of action of two antiplasmodial compounds, ellagic acid and 3,4,5-trimethoxyphenyl (6′-O-galloyl)-β-D-glucopyranoside (TMPGG), we studied in vitro two metabolic reactions of intraerythrocytic parasites: the activity of recombinant plasmepsin II, one of the haemoglobin proteases, and the detoxification of haematin into β-haematin. Both compounds inhibited plasmepsin II activity, but at concentrations ten-fold higher than those needed for inhibiting parasite growth. Moreover, ellagic acid inhibited the formation of β-haematin, with an IC50 only 3-fold higher than that of chloroquine. These data suggest that the antiplasmodial activity of ellagic acid could be related to the inhibition of β-haematin formation, whereas plasmepsin II does not represent the main target of the two compounds.