Proteasomes are essential proteolytic complexes in eukaryotic cells, playing key roles in protein homeostasis and parasite survival. While selective proteasome inhibition is already a validated strategy in diseases like malaria and schistosomiasis, its application to tick-borne diseases and their arthropod vectors remains underexplored. In this study, we demonstrate that proteasome inhibitors exert potent, multi-target effects against both ticks and tick-borne pathogens. Commercial inhibitors such as bortezomib and carfilzomib significantly suppressed the propagation of Babesia divergens (ex vivo) and Babesia microti (in vivo), and decreased Ixodes ricinus tick survival and motility by over 85% following membrane feeding with treated blood. Proteasome target engagement was confirmed by enzymatic activity assays and accumulation of polyubiquitylated proteins. We further screened several novel generations of peptide epoxyketone inhibitors derived from the marine natural product carmaphycin B, identifying compounds that achieved low-nanomolar inhibition of the Babesia β5 subunit while demonstrating a 20-fold selectivity index over human proteasomes and reduced cytotoxicity in HepG2 cells. These inhibitors effectively blocked Babesia growth in bovine erythrocyte cultures and, unexpectedly, also showed activity against Lyme disease causing Borrelia, further expanding their therapeutic potential. Building on analogies with Schistosoma mansoni, where selective β2 subunit targeting proved highly effective, we are currently expressing the Babesia 20S proteasome for cryo-EM structural studies and cleavage specificity profiling. Altogether, our findings validate the proteasome as a highly promising and dual-purpose therapeutic target—offering a novel strategy to combat both tick-borne diseases and the ticks that transmit them.