Carfilzomib (CFZ) is a potent second-generation proteasome inhibitor that blocks the ubiquitin-proteasome pathway, inducing apoptosis in cancer cells. Currently, commercially available CFZ formulations contain large amounts of excipients, require intravenous (IV) infusion, and have a short half-life of less than 1 h. Recent research trends have focused on developing alternative CFZ formulations to address these limitations; however, all attempts thus far have been restricted to injectable formulations. In this study, we developed a self-nanoemulsifying drug delivery system (SNEDDS) containing CFZ based on a Quality by Design (QbD) approach (CFZ-SN) to enhance the oral bioavailability of CFZ. The uniform, nanosized CFZ-SN droplets exhibited significantly improved water solubility and drug release profiles compared to raw CFZ. Furthermore, CFZ encapsulated in the optimized droplets demonstrated stability against enzymatic and lipolytic degradation in vivo. The uptake and permeation of CFZ-SN in enterocytes were notably enhanced through inhibition of the P-glycoprotein (P-gp) efflux pump. Additionally, CFZ-SN significantly increased cellular uptake and proteasome inhibition in cancer cells. Overall, our findings suggest that CFZ-SN has the potential to enable oral administration of CFZ, offering a promising alternative to existing injectable formulations.