Direct inhibition of the Keap1-Nrf2 protein-protein interaction (PPI) is a promising strategy for oxidative stress-related diseases, but the development of potent non-covalent inhibitors remains challenging. We designed a series of meta-substituted bis(arylsulfonamido)benzene derivatives by molecular hybridization of known Keap1-Nrf2 PPI inhibitors 2a and 3a. Compound 7a showed promising activity in the fluorescence polarization (FP) assay and was selected for structure-activity relationship (SAR) optimization. Modification of the core substituents and linker led to compound 13b, the most potent analogue in the series. Compound 13b inhibited the Keap1-Nrf2 interaction with IC₅₀ values of 183.4 nM in the FP assay and 107.5 nM in the TR-FRET assay. It also showed high metabolic stability, with 93.9% remaining after 30 min in human liver microsomes. These results identify 13b as a potent non-covalent Keap1-Nrf2 PPI inhibitor with a good balance of activity and metabolic stability, supporting further optimization of this scaffold.