Harmful cyanobacteria are a global environmental problem, yet we lack actionable understanding of toxigenic versus nontoxigenic strain ecology and toxin production. We performed a large-scale meta-analysis including 103 papers and used it to develop a mechanistic, agent-based model of Microcystis growth and microcystin production. Simulations for Lake Erie suggest that the observed toxigenic-to-nontoxigenic strain succession during the 2014 Toledo drinking water crisis was controlled by different cellular oxidative stress mitigation strategies (protection by microcystin versus degradation by enzymes) and the different susceptibility of those mechanisms to nitrogen limitation. This model, as well as a simpler empirical one, predicts that the planned phosphorus load reduction will lower biomass but make nitrogen and light more available, which will increase toxin production, favor toxigenic cells, and increase toxin concentrations.