Resumen: Land use/cover change (LUCC) and climate change (CC) affect water resource availability as they alter important hydrological processes. Mentioned factors modify the magnitude of surface runoff, groundwater recharge, and river flow among other parameters. In the present work, changes that occurred in the recent decades at the Quino and Muco river watersheds in the south-central zone of Chile were evaluated to predict future cover/use changes considering a forest expansion scenario according to Chilean regulations. In this way an expansion by 42.3 km2 and 52.7 km2 at Quino and Muco watersheds, respectively, was predicted, reaching a watersheds’ occupation of 35.4% and 22.3% in 2051. Additionally, the local climatic model RegCM4-MPI-ESM-MR was used considering periods from 2020–2049 and 2050–2079, under the RCP 8.5 scenario. Finally, the SWAT model was applied to assess the hydrological response of both watersheds facing the considered forcing factors. Five scenarios were determined to evaluate the LUCC and CC individual and combined effects. The results depict a higher sensitivity of the watersheds to CC impacts, where an increase of evapotranspiration, with a lessening of percolation, surface flow, lateral flow, and groundwater flow, triggered a water yield (WYLD) decrease in all predicted scenarios. However, when both global changes act synergistically, the WYLD decreases considerably with reductions of 109.8 mm and 123.3 mm at the Quino and Muco watersheds, respectively, in the most extreme simulated scenario. This water scarcity context highlights the necessity to promote land use management strategies to counteract the imminent effects of CC in the watersheds.