Climate change projections predict the increase of no-rain periods and storm intensity resulting in high hydrologic alteration of the Mediterranean rivers. Intermittent flow Rivers and Ephemeral Streams (IRES) are particularly vulnerable to spatiotemporal variation of climate variables, land use changes and other anthropogenic factors. In this work, the impact of climate change on the aquatic state of IRES is assessed by the combination of the hydrological model Soil and Water Assessment Tool (SWAT) and the Temporary Rivers Ecological and Hydrological Status (TREHS) tool under two different Representative Concentration Pathways (RCP 4.5 and RCP 8.5) using CORDEX model simulations. A significant decrease of 20–40% of the annual flow of the examined river (Tsiknias River, Greece) is predicted during the next 100 years with an increase in the frequency of extreme flood events as captured with almost all Regional Climate Models (RCMs) simulations. The occurrence patterns of hyporheic and edaphic aquatic states show a temporal extension of these states through the whole year due to the elongation of the dry period. A shift to the Intermittent-Pools regime type shows dominance according to numerous climate change scenarios, harming, as a consequence, both the ecological system and the social-economic one.