Phytoplankton production is an important factor in determining both ecosystem stability and the provision of ecosystem goods and services. The expansive and economically important North American Great Lakes are subjected to multiple stressors and understanding their responses to those stresses is important for understanding system-wide ecological controls. Here we show gradual increases in spring silica concentration (an indicator of decreasing growth of the dominant diatoms) in all basins of Lakes Michigan and Huron (USA and Canadian waters) between 1983 and 2008. These changes indicate the lakes have undergone gradual oligotrophication coincident with and anticipated by nutrient management implementation. Slow declines in seasonal drawdown of silica (proxy for seasonal phytoplankton production) also occurred, until recent years, when lake-wide responses were punctuated by abrupt decreases, putting them in the range of oligotrophic Lake Superior. The timing of these dramatic production drops is coincident with expansion of populations of invasive dreissenid mussels, particularly quagga mussels, in each basin. The combined effect of nutrient mitigation and invasive species expansion demonstrates the challenges facing large-scale ecosystems and suggest the need for new management regimes for large ecosystems.