Extreme weather conditions are associated with a variety of water quality issues that can pose harm to humans and aquatic ecosystems. Under dry extremes, contaminants become more concentrated in streams with a greater potential for harmful algal blooms, while wet extremes can cause flooding and broadcast pollution. Developing appropriate interventions to improve water quality in a changing climate requires a better understanding of how extremes affect watershed processes, and which places are most vulnerable. We developed a Soil and Water Assessment Tool model of the Cape Fear River Basin (CFRB) in North Carolina, USA, representing contemporary land use, point and non-point sources, and weather conditions from 1979 to 2019. The CFRB is a large and complex river basin undergoing urbanization and agricultural intensification, with a history of extreme droughts and floods, making it an excellent case study. To identify intervention priorities, we developed a Water Quality Risk Index (WQRI) using the load average and load variability across normal conditions, dry extremes, and wet extremes. We found that the landscape generated the majority of contaminants, including 90.1% of sediment, 85.4% of total nitrogen, and 52.6% of total phosphorus at the City of Wilmington’s drinking water intake. Approximately 16% of the watershed contributed most of the pollutants across conditions—these represent high priority locations for interventions. The WQRI approach considering risks to water quality across different weather conditions can help identify locations where interventions are more likely to improve water quality under climate change.