Climate change effects on long-term groundwater (GW) resource developments in the Tana Basin, Ethiopia, are a growing concern. Efforts to provide estimates under various climatic uncertainties are lacking in the region. To address this need, we deployed a fine-resolution (500 m) GW model using MODFLOW-NWT for the Tana Basin, Upper the Blue Nile region. The GW model was calibrated based on 98 historical instantaneous well-level measurements (RMSE = 16.36 m, 1.6% of range), and 38 years of monthly lake level data (RMSE = 0.2 m, 6.7% of range). We used the model to simulate long-term climate change impacts by considering two representative concentration pathways, (RCPs) 4.5 and 8.5, from the two extreme global circulation models (MIROC5 for wetter conditions and CSIRO-Mk3 for drier conditions) available in the region. While the MIROC5 simulated GW table (GWT) was found to be stable, the CSIRO-Mk3 simulated GWT exhibited large fluctuations within +2 m to −4 m by 2100 due to climate change. More critical impacts were predicted for the lake, where total lake releases from the baseline scenario were foreseen to be changed by +50% (MIROC5) or −22% (CSIRO-Mk3) by the end of 2100.