Lactobacillus plantarum FS5-5 (L. plantarum FS5-5) is a salt-tolerant probiotic strain, which had been isolated from northeast Chinese traditionally fermented Dajiang. We analyzed the underlying molecular mechanisms of L. plantarum FS5-5 after salt stress by isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics and bioinformatics analysis. L. plantarum FS5-5 was treated with low (1.5, 3.0, 4.0, and 5.0% (w/v) NaCl) and high (6.0, 7.0, and 8.0% (w/v) NaCl) salt stress. Differentially expression proteins (DEPs) of all groups were measured by quantitative proteomic approach of iTRAQ with LC–MS/MS. Furthermore, DEPs were identified by Mascot and GO, and bioinformatics analysis was conducted by KEGG. Thirty DEPs (P < 0.05) between low salt stress and control condition (0% (w/v) NaCl) were mapped and classified into nine functional groups; 122 DEPs (P < 0.05) between high salt stress and control condition were mapped and classified into 15 functional groups. In all groups, most proteins were involved in amino acid metabolism, carbohydrate metabolism, nucleotide metabolism, and ATP-binding cassette (ABC) transporter. We found that six proteins (metS, GshAB, GshR3, PepN, GshR4, and serA) involved in amino acid metabolism, three proteins (I526_2330, Gpd, and Gnd) involved in carbohydrate metabolism, and one protein (N876_0118940) involved in peptidoglycan hydrolysis were upregulated after salt stress. Conclusively, optimal L. plantarum FS5-5 growth was dependent on the collective action of different regulatory systems, with each system playing an important role in adapting to salt stress. There may be some relationship between the upregulated proteins of L. plantarum FS5-5 and salt stress.