3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound <b>22</b> exhibited excellent antiplasmodial <i>in vitro</i> activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains of<i>Plasmodium falciparum</i> (with IC<sub>50</sub> values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, <b>22</b> showed strong <i>in vivo</i> activity in the<i>Plasmodium berghei</i> mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in <i>P. falciparum</i>.