Systematic uncertainty analysis (UA) has rarely been conducted for integrated modeling of surface water-groundwater (SW-GW) systems, which is subject to significant uncertainty, especially at a large basin scale. The main objective of this study was to explore an innovative framework in which a systematic UA can be effectively and efficiently performed for integrated SW-GW models of large river basins and to illuminate how process understanding, model calibration, data collection, and management can benefit from such a systematic UA. The framework is based on the computationally efficient Probabilistic Collocation Method (PCM) linked with a complex simulation model. The applicability and advantages of the framework were evaluated and validated through an integrated SW-GW model for the Zhangye Basin in the middle Heihe River Basin, northwest China. The framework for systematic UA allows for a holistic assessment of the modeling uncertainty, yielding valuable insights into the hydrological processes, model structure, data deficit, and potential effectiveness of management. The study shows that, under the complex SW-GW interactions, the modeling uncertainty has great spatial and temporal variabilities and is highly output-dependent. Overall, this study confirms that a systematic UA should play a critical role in integrated SW-GW modeling of large river basins, and the PCM-based approach is a promising option to fulfill this role.