A library of known aspartic protease inhibitors was screened to identify compounds that inhibit plasmepsin V from Plasmodium vivax. This screen revealed compounds with an imino‐pyrimidinone‐fused pyrrolidine (IPF) scaffold that exhibited sub‐micromolar inhibitory activity against plasmepsin V. Further screening of IPF analogs against the related aspartic protease plasmepsin X showed inhibitory activity, while a third aspartic protease, plasmepsin IX, was not significantly inhibited. Modifications to the P1 biaryl region of the IPF scaffold differentially modulated inhibition of both plasmepsin V and X. Notably, analogs with potent plasmepsin X inhibitory activity successfully blocked the growth of Plasmodium falciparum in vitro. X‐ray structures of IPF analogs in complex with plasmepsin V provided insights into their binding mode and revealed avenues to further improve IPF potency and selectivity between plasmepsin V and X. This understanding of how these compounds interact with the active sites of plasmepsin V and X will serve as a foundation for the future design of dual inhibitors targeting these proteases.