Climate and land use and land cover (LULC) changes will impact watershed-scale water resources. These systemic alterations will have interacting influences on water availability. A probabilistic risk assessment (PRA) framework for water resource impact analysis from future systemic change is described and implemented to examine combined climate and LULC change impacts from 2011–2100 for a study site in west-central Texas. Internally, the PRA framework provides probabilistic simulation of reference and future conditions using weather generator and water balance models in series—one weather generator and water balance model for reference and one of each for future conditions. To quantify future conditions uncertainty, framework results are the magnitude of change in water availability, from the comparison of simulated reference and future conditions, and likelihoods for each change. Inherent advantages of the framework formulation for analyzing future risk are the explicit incorporation of reference conditions to avoid additional scenario-based analysis of reference conditions and climate change emissions scenarios. In the case study application, an increase in impervious area from economic development is the LULC change; it generates a 1.1 times increase in average water availability, relative to future climate trends, from increased runoff and decreased transpiration.