About 50% of U.S. water pollution problems are caused by non-point source (NPS) pollution, primarily sediment and nutrients from agricultural areas, despite the widespread implementation of agricultural Best Management Practices (BMPs). However, the effectiveness of implementation strategies and type of BMPs at watershed scale are still not well understood. In this study, the Soil and Water Assessment Tool (SWAT) ecohydrological model was used to assess the effectiveness of pollutant mitigation strategies in the Raccoon River watershed (RRW) in west-central Iowa, USA. We analyzed fourteen management scenarios based on systematic combinations of five strategies: fertilizer/manure management, changing row-crop land to perennial grass, vegetative filter strips, cover crops and shallower tile drainage systems, specifically aimed at reducing nitrate and total suspended sediment yields from hotspot areas in the RRW. Moreover, we assessed implications of climate change on management practices, and the impacts of management practices on water availability, row crop yield, and total agricultural production. Our results indicate that sufficient reduction of nitrate load may require either implementation of multiple management practices (38.5% with current setup) or conversion of extensive areas into perennial grass (up to 49.7%) to meet and maintain the drinking water standard. However, climate change may undermine the effectiveness of management practices, especially late in the 21st century, cutting the reduction by up to 65% for nitrate and more for sediment loads. Further, though our approach is targeted, it resulted in a slight decrease (~5%) in watershed average crop yield and hence an overall reduction in total crop production, mainly due to the conversion of row-crop lands to perennial grass. Such yield reductions could be quite spatially heterogeneously distributed (0 to 40%).