Melatonin (N-acetyl-5-methoxytryptamine) is an indole-like hormone that plays a pivotal role in the growth, development, and stress response of plants. Thus, investigating the underlying mechanisms of action and growth regulators involved, is imperative to enhance crop salt tolerance. In this study, seedlings of melon (Cucumis melo L.) grown in hydroponic solution were treated with control (CK), melatonin (50 & mu;M melatonin, MT), salt (60 mM NaCl, ST) and salt with melatonin (60 mM NaCl combined with 50 & mu;M melatonin, MS). The growth potentials including fresh weight, plant height, leaf area and stem diameter, and photosynthesisassociated parameters, and chlorophyll and lipid peroxidation contents of melon seedlings were measured. IP: 203.8 109 20 On: Tue 13 Jun 2023 07:08:54 Transcriptome analysis was performed and a library of differentially expessed genes (DEGs) between ST Copyright American Scientific Pub shers and MS treatments was screened. Both geneontology (GO) and Kyoto Encyclopedia of Genes and Genomes Delivered by Ingenta (KEGG) analyses were conducted for these DEGs. Finallly, qRT-PCR assay was performed for verification. The results showed that the growth potentials of melon seedlings treated with MS were significantly better than those of melatonin-free seedlings. Melatonin also moderately alleviated the NaCl-induced oxidative damage. KEGG enrichment analysis emphasized remarkably enriched pathways, which were strongly linked to photosynthesis, signal transduction and phytohormone synthesis. The functional genes in objective KEGG pathways were determined, including PsbY, AUX1, CYCD3, PYR/PRL and so on. The photosynthesis pathway (ko00195) was simultaneously significant in both comparison groups (18 and 3 genes, respectively). Furthermore, several families of transcription factors involved in reaction processes were mainly MYB, AP2EREBP, and bHLH families. It could be hypothesized that melatonin application effectively improve photosynthetic efficiency and facilitate the endogenous hormone metabolic networks to stimulate the growth of seedlings exposed to high salinity.