Agriculture is in dire need for effective solutions to adapt to the increasing salinity in soils and water reservoirs. The increase in salinity is already affecting crop production due to osmotic and ionic stresses. Research on the physiological and molecular responses activated by salinity is needed to elucidate the mechanism of tolerance to salinity. Such knowledge is essential to design solutions to be implemented into operational agriculture. Transcriptome profiling (RNA-Seq) has been proven a powerful tool to study physiological changes at the molecular level, and it has already been applied to study the transcriptomic profile of genotypes under varied stress conditions. In temperate fruit tree species, tree grafting on salinity tolerant rootstocks is a common method to compensate for the cultivar saline sensitivity. Persimmon species have different levels of tolerance to salinity, making them an appropriate model to study the mechanism of salinity tolerance, and to provide knowledge on persimmon species' potential as salt tolerant rootstock. In this study, we conducted a physiological and transcriptomic profiling of roots and leaves in a persimmon species commonly used as rootstock, Diospyros lotus, grown under saline and control condition. Characterization of the physiological responses associated to saline-stress tolerance along with the genes expression changes in roots and leaves allowed identifying several salt-tolerance mechanisms: Ion transport, photosynthesis and respiration systems, ROS signaling, and thermospermine synthesis. Differences were clearly observed in putative genes related to both Ca2+ and K+ transport. Chloride channel protein-like genes were upregulated in leaves and roots of sensitive plants and correlated with chlorine leaf accumulation. With regard to photosynthesis and respiration genes, all differentially expressed genes in leaves were upregulated in the tolerant plants compared to the sensitive ones, where a reduced metabolism supported by lowered photosynthesis and respiration genes expression as well as a significant reduction in carbon fixation was detected. ROS detoxification was, also, upregulated in both control and tolerant leaves, probably resulting in higher ROS content in the leaves of sensitive plants, probably as a part of a signaling mechanism that indicates high level of stress. Furthermore, an overexpression of thermospermine synthase was found in the roots of tolerant plants, which may be an indication that alterations in root architecture could act as an additional mechanism of response to salt stress.