Shallow groundwater acts as an important source of water for the ecosystem, agriculture, drinking water supply, etc.; it is, however, among those water resources most sensitive to climate change, and especially to aridification. In the present study, the delineation of regional recharge and discharge zones of the Danube–Tisza Interfluve (Hungary, 8000 km2) is presented via the combination of multivariate time series and geomathematical methods to explore the subregions most sensitive to dewatering. The shallow groundwater level time series of 190 wells, covering a semicentennial period (1961 to 2010), were grouped into three validated clusters representing characteristically different subregions. Then, the subregions’ means and individual shallow groundwater level time series were investigated for long-term trends and compared with local meteorological variability (precipitation, evapotranspiration, etc.) to determine their regime characteristics. As a result, shallow recharge and discharge zones, a gravity-driven flow system, and the discharge zone of a deeper, overpressured flow system could be discerned with distinctive long-term changes in water levels. The semicentennial trends in shallow groundwater levels were significant (p < 0.05) in the recharge (−0.042 m y−1) and in the overpressured discharge zone (0.009 m y−1), and insignificant in the rest of the area (−0.005 m yr−1). The present results concur with previous findings from the area but provide a statistically sound and reproducible delineation of the regime areas on a much finer scale than before. With the determination of the different climatic processes driving the semicentennial trends prevailing in the shallow groundwater, the high vulnerability of the recharge zone is underlined, while the outlined overpressured flow system seems to act independently from semicentennial precipitation trends. This study provides a more in-depth picture of the long-term changes in shallow groundwater and its drivers in of one of the most important agricultural areas in Hungary. It outlines, in a generally applicable way, the most vulnerable subareas for irrigation relaying on shallow groundwater extraction. In addition, the results can help adaptation-strategy decision makers to initiate a more effective and area-focused intervention in the case of the predicted negative trends for vulnerable recharge areas under various climate change scenarios.