Land use and climate are two determinant factors of water yield within a watershed. Understanding the effects of these two variables is key for the decision-making process within watersheds. Hydrologic modeling can be used for this purpose and the integration of future climate scenarios to calibrated models widens the spectrum of analysis. Such types of studies have been carried out in many areas of the world, including the Amazon Basin of South America. However, there is a lack of understanding on the effect of land use/land cover and climate change on Andean watersheds of this continent. Our study focused on the evaluation of water yield under different land use and climate scenarios using the semi-distributed hydrological model known as the Soil and Water Assessment Tool (SWAT) model. We worked on the Tona watershed (Colombia, South America), the most important source of water for a metropolitan population. Our results compared water yield estimates for historical conditions (1987–2002) with those of future combined scenarios for land use and climate for the 2006–2050 period. The modeling effort produced global estimates of water yield (average annual values) and, at the subwatershed level, identified strategic areas on which the protection and conservation activities of water managers can be focused.