The Grand River watershed (GRW) is an important agricultural area in Southern Ontario. Land use has been modified by various human endeavors, altering hydrology and increasing export of sediment and nutrients. The objective of this study was to predict spatial and temporal patterns of hydrology, and export of sediment and nutrients from the GRW to Lake Erie using the Soil and Water Assessment Tool (SWAT) model. The Sequential Uncertainty FItting (SUFI2) program was used to calibrate and validate stream flow for years 2001–2010. Calibration and validation of the SWAT model for monthly stream flow at York indicated good model performance (R2, NSE, and PBIAS = 0.64, 0.63 and 7.1 for calibration (2001–2005); = 0.82, 0.74 and 0.2, for validation (2006–2010)). The model was applied to predict sediment and nutrient export from the GRW into Lake Erie. Predicted loading at Dunnville (near the mouth) was 2.3 × 105 tonnes y−1 total suspended sediment, 7.9 × 103 tonnes y−1 TN, and 2.3 × 102 tonnes y−1 TP. This SWAT model can now be used to investigate the relative effects of best management practices, and to forecast effects of climate change, on sustainable water management, hydrology, and sediment and nutrient export to Lake Erie.