Climate warming globally has a profound effect on the hydrological regime, amplifying evapotranspiration and precipitation and accelerating the processes of snow melt and permafrost thaw. However, in the context of small river basins—those encompassing less than 10,000 km2—the response of the hydrological regime to climate change is intricate and has not yet been thoroughly understood. In this study, the Zhizdra River Basin, a typical small river basin in the eastern European plain with a total drainage area of 6940 km2, was selected to investigate the long-term variability of the hydrological regime and its responses to climate warming. Our results show that during the period of 1958–2016, the average runoff in the Zhizdra River Basin was approximately 170 mm, with significant fluctuations but no trend. Sensitivity analysis by the Budyko framework revealed that the runoff was more sensitive to changes in precipitation (P) compared to potential evapotranspiration (E0), implying that the Zhizdra River Basin is limited by water availability and has a slightly dry trend. A comprehensive analysis based on the seasonality of hydrometeorological data revealed that temperature predominantly affects spring runoff, while P mainly controls autumn runoff. Both factors make significant contributions to winter runoff. In response to climate change, the nonuniformity coefficient (Cv) and concentration ratio (Cn) of runoff have noticeably declined, indicating a more stabilized and evenly distributed runoff within the basin. The insights gleaned from this research illuminate the complex hydrological responses of small river basins to climate change, underlining the intricate interrelation among evapotranspiration, precipitation, and runoff. This understanding is pivotal for efficient water resource management and sustainable development in the era of global warming.