Trehalose can effectively protect the biomolecular structure, maintain the balance of cell metabolism, and improve the tolerance to various abiotic stresses in plants. However, the molecular mechanism underlying the improvement in salt tolerance by exogenous trehalose in watermelon (Citrullus lanatus) seedlings is still unclear. To understand these molecular mechanisms, in this study, watermelon seedlings under salt stress were treated with various concentrations of exogenous trehalose. An amount of 20 mM exogenous trehalose significantly improved the physiological status; increased the activities of enzymes such as POD, SOD, and CAT; and increased the K+/Na+ ratio in watermelon seedlings under salt stress. RNA-seq and metabolomic analysis were performed to identify the specifically expressed genes and metabolites after trehalose treatment. Watermelon seedlings were divided into salt stress (CK2), control (CK1) and trehalose treatment (T) groups as per the treatment. Overall, 421 shared differentially expressed genes (DEGs) were identified in the two comparison groups, namely CK2–CK1 and T–CK2. Functional annotation and enrichment analysis revealed that the DEGs were mainly involved in MAPK signaling pathway for plant hormone signal transduction and phenylpropanoid biosynthesis. Furthermore, 129 shared differential expressed metabolites (DEMs) were identified in the two comparison groups using liquid chromatography–mass spectrometry, which were mainly involved in the metabolic pathway and phenylpropanoid biosynthesis. The combined transcriptomic and metabolomic analyses revealed that genes involved in phenylpropanoid biosynthesis, plant hormone signal transduction, and carbohydrate biosynthesis pathways, especially bHLH family transcription factors, played an important role in improving salt tolerance of watermelon seedlings after exogenous trehalose treatment.