Updated project metadata. Vanillin is one of the major phenolic inhibitors of Saccharomyces cerevisiae in lignocellulosic hydrolysates. Deleting transcription factor gene YRR1 improves vanillin resistance by promoting some translation-related processes that were confirmed at the transcription level in our previous studies. In this work, we investigated the effect of proteomic change on vanillin stress and YRR1 deletion. In wild-type cells, vanillin reduced the number of ribosomal proteins and thereby inhibited cells’ translation. YRR1 deletion increased 112 protein quantities; 48 of 112 up-regulated proteins are involved in the stress response, translational and basal transcriptional regulation. Fermentation data showed that the overexpression of HAA1, MBF1, and TMA17, which encode transcriptional activator, coactivator, and proteasome assembly chaperone, respectively, enhanced resistance to vanillin in S. cerevisiae. These results enriched the perspective of molecular mechanisms for YRR1 deletion to protect yeast from vanillin stress and offered novel targets for designing inhibitor-resistant ethanologenic yeast strains.