This study examines the hydrological dynamics of the Ticino irrigation cascade in northern Italy from 2004 to 2022. The region, which is shaped by human activity, is characterized by its flat topography and complex management of water resources, featuring a unique historic irrigation cascade. Utilizing the Soil and Water Assessment Tool (SWAT), we investigated the water availability during recent severe droughts in this complex agricultural environment, which lacks natural drainage. This area faces risks due to increasing temperatures and increased rainless days. Therefore, understanding the soil water dynamics is essential for maintaining the system’s sustainability. Calibrating and validating the SWAT model with runoff data was challenging due to the absence of natural drainage. Thus, we utilized MOD16 evapotranspiration (AET) data for calibration. Generally, the calibration and validation of the SWAT model yielded satisfactory results in terms of the Kling–Gupta efficiency (KGE). Despite some discrepancies, which were mainly related to the data sources and resolution, the calibrated model’s outputs showed increased actual evapotranspiration that was influenced by climate and irrigation, leading to water deficits and droughts. The soil water content (SWC) decreased by 7% over 15 years, impacting crop productivity and environmental sustainability. This also resulted in rising water stress for crops and the ecosystem in general, highlighting the direct impact of adverse climate conditions on soil hydrology and agriculture. Our research contributes to the understanding of soil–water dynamics, as it specifically addresses recent droughts in the Lombardy lowlands.