• The adaptive irrigation behaviors might worsen the water scarcity in the CRB. • Clustering identified bold, prudent, and forward-looking farmer classes. • We indicated specific parameters for uncertainty reduction in human systems. The Colorado River Basin (CRB) supports the water supply for seven states and forty million people in the Western United States (US) and has been suffering an extensive drought for more than two decades. As climate change continues to reshape water resources distribution in the CRB, its impact can differ in intensity and location, resulting in variations in human adaptation behaviors. The feedback from human systems in response to the environmental changes and the associated uncertainty is critical to water resources management, especially for water-stressed basins. This paper investigates how human adaptation affects water scarcity uncertainty in the CRB and highlights the uncertainties in human behavior modeling. Our focus is on agricultural water consumption, as approximately 80% of the water consumption in the CRB is used in agriculture. We adopted a coupled agent-based and water resources modeling approach for exploring human-water system dynamics, in which an agent is a human behavior model that simulates a farmer’s water consumption decisions. We examined uncertainties at the system, agent, and parameter levels through uncertainty, clustering, and sensitivity analyses. The uncertainty analysis results suggest that the CRB water system may experience 13 to 30 years of water shortage during the 2019–2060 simulation period, depending on the paths of farmers’ adaptation. The clustering analysis identified three decision-making classes: bold, prudent, and forward-looking, and quantified the probabilities of an agent belonging to each class. The sensitivity analysis results indicated agents whose decision-making models require further investigation and the parameters with the higher uncertainty reduction potentials. By conducting numerical experiments with the coupled model, this paper presents quantitative and qualitative information about farmers’ adaptation, water scarcity uncertainties, and future research directions for improving human behavior modeling.