The increasing gap between water demands and availability is a significant challenge for sustainable water management, particularly in the context of growing irrigation needs driven by climate change. In the Côa region (inner-north Portugal), agriculture plays a vital role in the local economy, ensuring food security and contributing to the conservation of natural resources, though also threatened by climate change. The present study assesses how streamflow in the Côa River can be affected by climate change. The HSPF (Hydrological Simulation Program-FORTRAN) hydrological model was coupled with three global–regional climate model chains to simulate historical monthly and annual streamflow (1986–2015), and to predict future (2040–2099) streamflow under RCP8.5. Irrigation scenarios were subsequently developed considering a potential future increase from 10% to 50% per decade. The evaluation of HSPF performance during the historical period revealed good agreement (R2 > 0.79) between simulated and observed flows. A general decrease in streamflow is found in the future, particularly in 2070–2099, with annual mean streamflow projected to decrease by −30% until 2099. Interannual variability is also expected to increase. Generally, the simulations indicated higher future flows in winter/early spring, whilst they are expected to decrease over the rest of the year, suggesting drought intensification. An increase in water demands for irrigation, potentially rising from 46 hm3·yr−1 (baseline scenario) up to 184 hm3·yr−1 (50% increase per decade) may lead to unsustainable irrigation. Managing these opposite trends poses significant challenges, requiring a comprehensive and integrated approach from stakeholders and policymakers. Strategies should focus on both demand-side and supply-side measures to optimize water use, improve water efficiency, and preserve water availability.