Significance There is an urgent need for alternative antimalarials with the emergence of artemisinin-resistant malaria parasites. Blocking sugar uptake in Plasmodium falciparum by selectively inhibiting the hexose transporter P. falciparum hexose transporter 1 (PfHT1) kills the blood-stage parasites without affecting the host cells, making PfHT1 a promising therapeutic target. Here, we report the development of a series of small-molecule inhibitors that simultaneously target the orthosteric and the allosteric binding sites of PfHT1. These inhibitors all exhibit selective potency on the P. falciparum strains over human cell lines. Our findings establish the basis for the rational design of next-generation antimalarial drugs.