AbstractHere, we present remarkable epoxyketone‐based proteasome inhibitors with low nanomolar in vitro potency for blood‐stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000‐fold greater selectivity for erythrocytic‐stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D‐amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171‐fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti‐malarial drugs.