Updated project metadata. Malaria remains a global health threat as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome beta5 active-site. A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (Minimum Inoculum of Resistance >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto beta7. Inhibition of Pfbeta5 correlated with parasite killing, without inhibiting the human proteasome or showing cytotoxicity. The Pf_proteasome_SW584 cryo-EM structure showed SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the beta5/beta6/beta3 subunit interface that shows species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity, provides a path for drugging this essential target.