Climate change caused by the increase in greenhouse gas in the atmosphere has significantly influenced the water balance by causing a change in precipitation, temperature, and evaporation rate. This study aimed to assess the status of climate change and hydrological responses to climate change using the International Atomic Energy Agency Water balance Model with Isotopes (IWBMIso). The IWBMIso model is a lake coupled with catchment, a spatially distributed monthly water balance model that considers water fluxes and storages and their associated isotopic compositions. Climate Research Unit (CRU) climate data and Representative Concentration Pathway (RCP4.5 and RCP8.5) climate scenarios from European Community Earth System Modeling (EC-Earth) General Circulation Model (GCM) were used in the modeling processes. The performances of CRU and EC-Earth climate data were validated against the observed climate data using statistical metrics before analyzing climate change and hydrological characteristics. Climate scenario data were divided into four windows of 30 years each from 1975-2100. The period from 1975-2005 was taken as a baseline period against which a comparison was made and the rest are future time horizons: 2020(2006-2036), 2050(2037-2067), and 2080(2068-2100). The downscaled EC-Earth climate outputs were used as an input into the IWBMIso model to assess climate change and hydrological responses. Based on monthly data of precipitation, maximum and minimum temperature, relative humidity, evapotranspiration, MODIS Normalized Difference Vegetation Index (NDVI), MODIS vegetation continuity field, soil data, and isotope precipitation were run using IWBMIso for baseline period and future time horizons. Isotope compositions were used for calibration and to evaluate the performances of calibration results. The IWBMIso model was calibrated and validated against the observed data. The calibration result reveals that (Coefficient of determination (R2) = 0.78, Nash-Sutcliffe (NS) =0.7 and Willmott index of agreement (d) = 0.93) and the validation results are (R2=0.82, NS =0.64 and d = 0.92. The result revealed that precipitation did not show a steady increase or decrease in all-time horizons on a monthly basis. In the meantime, the annual precipitation rate shows an increasing trend in all-time horizons except at the beginning of the century under the Representative Concentration Pathway (RCP4.5) scenario. However, the maximum and minimum temperature shows an increasing trend in all-time horizons in the future monthly and annually. Lake Evapotranspiration result reveals the increment trend under all scenarios (RCP4.5& RCP8.5) both monthly and annually. The reason for this is that straightforward temperatures are linked to the rising of evapotranspiration. The major rivers; Gilgel Abbay, Gummara, Megech, and Ribb that inflows to the Lake Tana, and Abbay/Blue Nile/ the only river that outflow from the Lake Tana, shows inconsistent stream flows trend, especially on monthly flow in all time horizons. However, in terms of annual flow rate, these major rivers show an incremental trend especially at the mid and end of the century. Lake Tanaâ€™s water level is inconsistent on monthly basis. However, the annual Lake Tana water level shows an increasing trend at the mid and end of the century in all scenarios. In conclusion, the hydrology of the Lake Tana sub-basin is highly vulnerable to climate change, especially on monthly basis. However, the impacts are moderate annually in all time horizons. In the future, climate change and its impact on the environment must therefore be seen regularly to be considering the effect for planning and decision-making.