Sesame is one of the most important oilseed crops and has high nutritional value. The yield and quality of sesame are severely affected by high salinity in coastal and semi-arid/arid regions. In this study, the phenotypic, physiological, and proteomic changes induced by salt treatment were analyzed in salt-tolerant (G441) and salt sensitive (G358) seedlings. Phenotypic and physiological results indicated that G441 had an enhanced capacity to withstand salinity stress compared to G358. Proteomic analysis revealed a strong induction of salt-responsive protein species in sesame, mainly related to catalytic, hydrolase, oxidoreductase, and binding activities. Pathway enrichment analysis showed that more salt-responsive proteins in G441 were involved in tyrosine metabolism, carbon fixation in photosynthetic organisms, carbon metabolism, alpha-linolenic acid metabolism, biosynthesis of amino acids, photosynthesis, and glutathione metabolism. Furthermore, G441 displayed unique differentially accumulated proteins in seedlings functioning as heat shock proteins, abscisic acid receptor PYL2-like, calcium dependent protein kinases, serine/threonine-protein phosphatases, nucleoredoxin, and antioxidant enzymes. Quantitative real-time PCR analysis revealed that some of the proteins were also regulated by salinity stress at the transcript level. Our findings provide important information on salinity responses in plants and may constitute useful resources for enhancing salinity tolerance in sesame. Significance: Our study identified potential biological pathways and salt-responsive protein species related to transducing stress signals and scavenging reactive oxygen species under salt stress. These findings will provide possible participants/pathways/proteins that contribute to salt tolerance and may serve as the basis for improving salinity tolerance in sesame and other plants.