Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised be resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorate dehydrogenase that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing napthyl (DSM1) or anthracenyl (DSM2), plama exposure was reduced upon repeated dosing. Phenyl-substituted traizolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.