The need for novel antimalarials is apparent given the continuing disease burden worldwide, despite significant drug discovery advances from the bench to the bedside. In particular, small-molecule agents with potent efficacy against both the liver and blood stages of Plasmodium parasite infection are critical for clinical settings as they would simultaneously prevent and treat malaria with a reduced selection pressure for resistance. While experimental screens for such dual-stage inhibitors have been conducted, the time and cost of these efforts limit their scope. Here, we have focused on leveraging machine learning approaches to discover novel antimalarials with such properties. A random forest modeling approach was taken to predict small molecules with in vitro efficacy versus liver-stage Plasmodium berghei parasites and a lack of human liver cell cytotoxicity. Empirical validation of the model was achieved with the realization of hits with liver-stage efficacy after prospective scoring of a commercial diversity library and consideration of structural diversity. A subset of these hits also demonstrated promising blood-stage Plasmodium falciparum efficacy. These 18 validated dual-stage antimalarials represent novel starting points for drug discovery and mechanism of action studies with significant potential for seeding a new generation of therapies.