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Abstract Background The 2-phenylethanol (2-PE) tolerance phenotype is crucial to the production of 2-PE, and Pdr1p mutation can significantly increase the tolerance of 2-PE in Saccharomyces cerevisiae. However, its underlying molecular mechanisms are still unclear, hindering the rational design of superior 2-PE tolerance performance. Results Here, the physiology and biochemistry of the PDR1_862 and 5D strains were analyzed. At 3.5 g/L 2-PE, the ethanol concentration of PDR1_862 decreased by 21%, and the 2-PE production of PDR1_862 increased by 16% than those of 5D strain. Transcriptome analysis showed that at 2-PE stress, Pdr1p mutation increased the expression of genes involved in the Ehrlich pathway. In addition, Pdr1p mutation attenuated sulfur metabolism and enhanced the one-carbon pool by folate to resist 2-PE stress. These metabolic pathways were closely associated with amino acids metabolism. Furthermore, at 3.5 g/L 2-PE, the free amino acids content of PDR1_862 decreased by 31% than that of 5D strain, among the free amino acids, cysteine was key amino acid for the enhancement of 2-PE stress tolerance conferred by Pdr1p mutation. Conclusions The above results indicated that Pdr1p mutation enhanced the Ehrlich pathway to improve 2-PE production of S. cerevisiae, and Pdr1p mutation altered the intracellular amino acids contents, in which cysteine might be a biomarker in response to Pdr1p mutation under 2-PE stress. The findings help to elucidate the molecular mechanisms for 2-PE stress tolerance by Pdr1p mutation in S. cerevisiae, identify key metabolic pathway responsible for 2-PE stress tolerance.