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This study integrates 90 years of hydrometeorological observations (1930/31–2019/20) with end-century projections (2080–2099) to evaluate climate-driven changes in the water balance of the Nitra River basin (2094 km2), Slovakia. Despite a modest 2–3% increase in annual precipitation from 1930/31–1959/60 to 1990/91–2019/20, mean annual runoff declined from 229 mm to 201 mm (≈−12%), primarily due to enhanced evapotranspiration stemming from a +1.08 °C basin-wide temperature increase. An empirical regression from 90 hydrological years shows that +100 mm in precipitation boosts runoff by ≈41 mm, while +1 °C in temperature reduces it by ≈13 mm. The BILAN monthly water balance model was calibrated for 1930/31–2019/20 to decompose runoff components. Over the 90-year period, the modeled annual runoff averaged 222 mm, comprising a 112 mm baseflow (50.4%), a 91 mm interflow (41.0%), and a 19 mm direct runoff (8.6%), underscoring the key role of groundwater and subsurface flows in sustaining streamflow. In the second part of our study, the monthly water balance model BILAN was recalibrated for 1995–2014 to simulate future runoff under three CMIP6 Shared Socioeconomic Pathways. Under the sustainability pathway SSP1-1.9 (+0.88 °C; +1.1% precipitation), annual runoff decreases by 8.9%. The middle-of-the-road scenario SSP2-4.5 (+2.6 °C; +3.1% precipitation) projects a 17.5% decline in annual runoff, with particularly severe reductions in autumn months (September −32.3%, October −35.8%, December −40.4%). The high-emission pathway SSP5-8.5 (+5.1 °C; +0.4% precipitation) yields the most dramatic impact with a 35.2% decrease in annual runoff and summer deficits exceeding 45%. These results underline the extreme sensitivity of a mid-sized Central European basin to temperature-driven evapotranspiration and the critical importance of emission mitigation, emphasizing the urgent need for adaptive water management strategies, including new storage infrastructure to address both winter floods and intensifying summer droughts.