Cyanobacterial harmful algal blooms (CyanoHABs) have serious adverse effects on human and environmental health. Herein, we developed a modeling framework that predicts the effect of climate change on cyanobacteria concentrations in large reservoirs in the contiguous U.S. The framework, which uses climate change projections from five global circulation models, two greenhouse gas emission scenarios, and two cyanobacterial growth scenarios, is unique in coupling climate projections with a hydrologic/water quality network model of the contiguous United States. Thus, it generates both regional and nationwide projections useful as a screening-level assessment of climate impacts on CyanoHAB prevalence as well as potential lost recreation days and associated economic value. Our projections indicate that CyanoHAB concentrations are likely to increase primarily due to water temperature increases tempered by increased nutrient levels resulting from changing demographics and climatic impacts on hydrology that drive nutrient transport. The combination of these factors results in the mean number of days of CyanoHAB occurrence ranging from about 7 days per year per waterbody under current conditions, to 16–23 days in 2050 and 18–39 days in 2090. From a regional perspective, we find the largest increases in CyanoHAB occurrence in the Northeast U.S., while the greatest impacts to recreation, in terms of costs, are in the Southeast.