Climate change is unquestionably a very important challenge facing the world in the 21st century due to its extensive impacts on the environment and socioeconomic situations of the global community. This study was conducted to evaluate the change in climate and its impact on water resources in the upper Blue Nile basin, Ethiopia. Climate data were projected by six Global Climate Models (GCMs) in the Coupled Model Intercomparison Project (CMIP5). Changes in temperature and rainfall and their impacts on PET, seasonal aridity, and stream flow of watersheds including the extreme flow events were evaluated by classifying the entire data into four categories. The data range consisting 1971–2000, was taken as a baseline, whereas the data ranges 2011–2040 (Period 1), 2041–2070 (Period 2), and 2071–2100 (Period 3) were considered as the targeted change study periods. Based on the assessment result, it was found that both the maximum temperature and minimum temperature are expected to increase in the region over the 21st century, with the highest increase in Period 3; whereas the change in rainfall showed seasonal fluctuation. The loss of water by PET is anticipated to increase due to the increase in temperature; consequently, it is also found that seasonal aridity is likely to increase prominently in the dry season. The future stream flow nature of watersheds is likely to be affected by climate change, with an increase in rainy/summer and post-summer seasons, and a decrease in dry season. It is also discovered that the low flows of watersheds are anticipated to exhibit a consistent decline throughout the 21st century, whereas, the high flow events are expected to increase across all watersheds.