The halophyte Suaeda salsa displayed strong resistance to salinity. Up to date, molecular mechanisms underlying tolerance of S. salsa to salinity have not been well understood. In the present study, S. salsa seedlings were treated with 30‰ salinity and then leaves and roots were subjected to Illumina sequencing. Compared with the control, 68,599 and 77,250 unigenes were significantly differentially expressed in leaves and roots in saline treatment, respectively. KEGG enrichment analyses indicated that photosynthesis process, carbohydrate, lipid and amino acid metabolisms were all downregulated in saline treatment, which should inhibit growth of S. salsa. Expression levels of Na+/H+ exchanger, V-H+ ATPase, choline monooxygenase, potassium and chloride channels were upregulated in saline treatment, which could relieve reduce over-accumulation of Na+ and Cl-. Fe-SOD, glutathione, L-ascorbate and flavonoids function as antioxidants in plants. Genes in relation to them were all upregulated, suggesting that S. salsa initiated various antioxidant mechanisms to tolerate high salinity. Besides, plant hormones, especially auxin, ethylene and jasmonic acid signaling transduction pathways were all upregulated in response to saline treatment, which were important to gene regulations of ion transportation and antioxidation. These changes might comprehensively contribute to tolerance of S. salsa to salinity. Overall, the present study provided new insights to understand the mechanisms underlying tolerance to salinity in halophytes.