Extreme weather is associated with a variety of water quality issues that can pose harm to humans and aquatic ecosystems. Under dry conditions, contaminants become concentrated in streams with a greater potential for harmful algal blooms, while wet conditions can cause flooding and broadcast pollution. Developing interventions to improve water quality in a changing climate requires a better understanding of how hydroclimatic variability affects 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, complex river basin undergoing urbanization and agricultural intensification, with a history of droughts and floods. To identify intervention priorities, we developed a Water Quality Risk Index (WQRI) using the average and variability of contaminant loads across dry, normal and wet conditions. The landscape generally contributed the majority of pollutants (e.g., via erosion, fertilizer and manure applications), including 90.1% of sediment, 83.2% of total nitrogen, and 52.4% of total phosphorus at the City of Wilmington's drinking water intake, yet point sources were influential during dry periods. Approximately 16% of the watershed contributed most of the pollutants across conditions—these represent priority locations for interventions such as restoration, urban, or agricultural best management practices. The WQRI approach considering risks to water quality across conditions can help identify locations where interventions are more likely to improve water quality under climate change.