Zygosaccharomyces rouxii is widely applied in the production of fermented foods, where salt stress is a common environmental condition encountered. In this study, salt stress response of Z. rouxii was investigated based on physiological and transcriptomic analyses, and the results showed that Z. rouxii evoked a global regulation to resist salt stress. Analysis of physiological data showed that salt stress led to accumulation of glycerol and trehalose, and increase of unsaturated fatty acids-proportions. Intracellular amino acid analysis showed that the content of 4 amino acids (threonine, tyrosine, lysine and proline) increased significantly and 2 amino acids (serine and lysine) decreased. In addition, scanning electron microscopy analyses showed that the cell surface of Z. rouxii became rough and cell wall ruptured accompanied by intracellular spillover after salt stress. Comparison of transcriptome data showed that the genes involved in cellular metabolism and ribosome biosynthesis exhibited differently expression, which is consistent with the results of physiological data. Results presented in this study may be helpful in understanding the salt tolerance mechanism of Z. rouxii, and provide theoretical support of its application during food fermentation.