A global dataset was compiled to examine relations between the total nitrogen to total phosphorus ratio (TN:TP) and microcystin concentration in lakes and reservoirs. Microcystin concentration decreased as TN:TP ratios increased, suggesting that manipulation of the TN:TP ratio may reduce microcystin concentrations. This relationship was experimentally tested by adding ammonium nitrate to increase the TN:TP ratio in large-scale (70 m3), in situ mesocosms located in a eutrophic reservoir that routinely experiences toxic blooms of cyanobacteria. At a TN:TP ratio >75:1, chlorophytes dominated the phytoplankton community in the mesocosms, while cyanobacterial biovolume was significantly reduced and microcystin was not detected. In contrast, the unmanipulated reservoir was dominated by cyanobacteria, and microcystin was detected. Secchi depths were 1.1 to 1.8 times greater in the mesocosms relative to the reservoir. Cladoceran zooplankton had a larger body size (0.14 mm on average) in the mesocosms compared to conspecifics in the reservoir, which was likely related to the higher quality food. Combined, these empirical and experimental data indicate that although nutrient addition is counterintuitive to current cyanobacteria management practices, increasing the TN:TP ratio by adding nitrogen may be a potential short-term management strategy to reduce cyanobacteria and cyanotoxins when other alternatives (e.g., phosphorus reduction) are not possible. Additional experimental studies with careful controls are needed to define best management practices and identify any potential unintended consequences before nitrogen addition is implemented as a lake and reservoir management practice.