Climate change is increasingly influencing the water cycle, hindering the effective management of water resources in various sectors. Lazio, central Italy, exhibits a wide range of climatic conditions, stretching from the Tyrrhenian coast to the Apennines. This study assessed a crucial aspect of climate change, focusing specifically on reference evapotranspiration (ETo) and its associated hydrological variables. The seasonal Mann–Kendall (MK) test was used to assess trends in gridded data. The K-means algorithm was then applied to divide Lazio into four homogeneous regions (clusters), each characterized by distinct trends in hydrological variables. The analysis revealed statistically significant increasing trends (p ≤ 0.01) in temperature, solar radiation, and ETo, with more marked effects observed in the coastal and hilly clusters. In contrast, statistically significant decreasing trends (p ≤ 0.01) were observed for relative humidity, while no statistically significant trends (p > 0.01) were observed for precipitation. This study’s methodology, combining trend analysis and clustering, provides a comprehensive view of ETo dynamics in Lazio, aiding in pattern recognition and identifying regions with similar trends.