Tomato (Solanum lycopersicum L.) is a model crop as well as an important food worldwide. In arid areas, increasing soil salinity has limited higher yields in tomato production. As a second messenger molecule, cyclic guanosine monophosphate (c-GMP) plays an indispensable role in plant response to salt stress by regulating cell processes to promote plant growth and development. However, this mechanism has not been fully explored in tomato seedlings. In this experiment, tomato seeds were cultured in four treatments: (I) distilled water (CK); (2) 20 mu M c-GMP (TI); (3) 50 mM NaCl (T2); and (4) 20 mu M c-GMP + 50 mM NaCl (T3). The results show that 20 mu M c-GMP effectively alleviated the inhibitory effect of 50 mM NaCl on growth and development, and induced the expression of 1580 differentially expressed genes (DEGs). Seedlings in the CK vs TI shared 95 upregulated and 442 downregulated DEGs, whereas T2 vs T3 shared 271 upregulated and 772 down regulated DEGs. Based on KEGG (Kyoto Encyclopaedia of Genes and Genomes) analysis, the majority of DEGs were involved in metabolism; exogenous c-GMP induced significant enrichment of pathways associated with carbohydrates, phenylpropanoids and fatty acid metabolism. Most PMEs, acCoA, PAL, PODs, FADs, and AD were upregulated, and GAPDHs, PL, PG, BXL4, and beta-G were downregulated, which reduced susceptibility of tomato seedlings to salt and promoted their salt tolerance. The application of c-GMP increased soluble sugar, flavonoid and lignin contents, reduced accumulation of malondialdehyde (MDA), and enhanced the activity of peroxidase (POD). Thus, our results provide insights into the molecular mechanisms associated with salt tolerance of tomato seedlings.