This paper describes the model simulation of a portion of the Huaihe Basin upstream of the river mouth at Hongze Lake, with an area of 130 520 km2. The MIKE 11 modeling system was used to assess the flows and water quality in the Huaihe, Shayinghe, Honghe, Guohe, and Pihe rivers. The hydraulic part of the model was used to study the propagation of flows in the Huaihe River, which was calibrated with data from 2002-2003 and verified with data from 2004-2005. In general, there was agreement between measured and simulated discharges at all the hydrological stations. Except for some places close to large gates, there was reasonable agreement between measured and simulated water levels in the simulated rivers. The MIKE 11 WQ (water quality) model was used to study general sanitary parameters describing the river water quality in areas influenced by human activities. The water quality model simulated dissolved oxygen (DO), chemical oxygen demand (COD) and ammonia nitrogen (NH3-N). The difference between the simulated and observed concentrations was within the range that could be expected from water quality modeling, taking into account uncertainties such as pollution loads, and monitoring and sampling frequency. This model setup was also suitable for the subsequent scenario modeling of periods of water project operation. In the simulation of the Pihe River, increasing the discharge at Hengpaitou Dam was shown to cause a significant improvement in water quality downstream of Lu’an City. In the Shayinghe and Huaihe rivers, the effect was less visible. This suggests that the poor water quality in the Huaihe Basin is mainly caused by extensive discharge of domestic and industrial wastewater.