Transport of excess nutrients and total suspended solids (TSS) such as sediment by freshwater systems has led to degradation of aquatic ecosystems around the world. Nutrient and TSS loads from Midwestern states to the Mississippi River are a major contributor to the Gulf of Mexico Hypoxic Zone, an area of very low dissolved oxygen concentration in the Gulf of Mexico. To better understand Indiana’s contribution of nutrients and TSS to the Mississippi River, annual loads of nitrate plus nitrite as nitrogen, total phosphorus, and TSS were calculated for nine selected watersheds in Indiana using the load estimation model, S-LOADEST. Discrete water-quality samples collected monthly by the Indiana Department of Environmental Management’s Fixed Stations Monitoring Program from 2000–2010 and concurrent discharge data from the U. S. Geological Survey streamflow gages were used to create load models. Annual nutrient and TSS loads varied across Indiana by watershed and hydrologic condition. Understanding the loads from large river sites in Indiana is important for assessing contributions of nutrients and TSS to the Mississippi River Basin and in determining the effectiveness of best management practices in the state. Additionally, evaluation of loads from smaller upstream watersheds is important to characterize improvements at the local level and to identify priorities for reduction.