Inhibitors of the Plasmodium falciparum proteasome (Pf20S) have the ability to kill malaria parasites in the blood and liver, although identifying compounds with sufficient parasite-selectivity has proven challenging. We report on the anti-plasmodial activity of a novel class of non-covalent proteasome inhibitors with the ability to spare mammalian cells. We assessed ex vivo sensitivities of 11 asparagine ethylenediamine peptidomimetic Pf20S inhibitors using fresh clinical isolates of P. falciparum collected in Tororo and Busia districts in Uganda from 2017-2019. IC50s were determined using a 72-h microplate growth inhibition assay with SYBR Green. We observed a range of Pf20S inhibitor potencies with geometric mean IC50s from 1.8 - 1900 nM (26 - 68 isolates tested per compound), with 6 of the compounds having mean IC50s < 100 nM. TDI8304, a lead compound with good drug-like properties, had a geometric mean IC50 of 18 nM with limited variability among 68 tested isolates (range = 6.0 - 23 nM). Significant and positive associations (r = 0.32 - 0.84; p < 0.05) were seen for IC50s between all inhibitors. We then tested for correlations between the Pf20S inhibitor IC50s and those of other experimental antimalarials provided by Medicines for Malaria Venture and a panel of standard antimalarials. Results for four Pf20S inhibitors were significantly and positively associated with IC50s of two mitochondria-targeted compounds, ELQ300 and proguanil (r = 0.38 - 0.71; p < 0.05). IC50 results for Pf20S inhibitors were not associated with common polymorphisms in the transporters PfMDR1 (N86Y, Y184F, D1246Y) and PfCRT (K76T). Sequencing in Ugandan isolates of the β5 and β6 subunits of the Pf20S proteasome, which are putative targets of these inhibitors, is underway. Our results show that Pf20S inhibitors demonstrated excellent potency against field isolates and may overlap in mechanisms of action and/or resistance with established antimalarials and other experimental compounds in development.