Histone deacetylases (HDACs) have been identified as emerging antiplasmodial drug targets. In this work, we report on the synthesis, structure-activity relationships, metabolic stability and in vivo efficacy of new peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. A mini library of HDAC inhibitors was synthesized using a one-pot, multi-component protocol or submonomer pathways. The screening of the target compounds for their activity against asexual blood stage parasites, human cell cytotoxicity, liver stage parasites, and selected human HDAC isoforms provided important structure-activity relationship data. The most promising HDAC inhibitor from this series, compound 3n, demonstrated potent activity against drug-sensitive and drug-resistant asexual stage P. falciparum parasites and was selective for the parasite versus human cells (Pf3D7 IC<sub>50</sub> 0.016 μM; SI<sup>HepG2/Pf3D7</sup> 573; PfDd2 IC<sub>50</sub> 0.002 μM; SI<sup>HepG2/PfDd2</sup> 4580) combined with activity against P. berghei exoerythrocytic liver stages (PbEEF IC<sub>50</sub> 0.48 μM). While compound 3n displayed high stability in human (Cl<sub>int</sub> 5 μL/min/mg) and mouse (Cl<sub>int</sub> 6 μL/min/mg) liver microsomes, only modest oral in vivo efficacy was observed in P. berghei infected mice. Together these data provide a foundation for future work to improve the properties of these dual-stage inhibitors as drug leads for malaria.