Here we report the nanomolar potencies of <i>N</i> <sup>1</sup>,<i>N</i> <sup>3</sup>-dialkyldioxonaphthoimidazoliums against asexual forms of sensitive and resistant <i>Plasmodium falciparum</i>. Activity was dependent on the presence of the fused quinone-imidazolium entity and lipophilicity imparted by the N<sup>1</sup>/N<sup>3</sup> alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC<sub>50</sub> < 1 μM. A representative analog with good solubility, limited PAMPA permeability, and microsomal stability demonstrated oral efficacy on a humanized mouse model of <i>P. falciparum</i>.