The availability of dissolved inorganic and organic nutrients and their transformations along the fresh to marine continuum are being modified by various natural and anthropogenic activities and climate-related changes. Subtropical central and eastern Florida Bay, located at the southern end of the Florida peninsula, is classically considered to have inorganic nutrient conditions that are in higher-than-Redfield ratio proportions, and high levels of organic and chemically-reduced forms of nitrogen. However, salinity, pH and nutrients, both organic and inorganic, change with changes in freshwater flows to the bay. Here, using a time series of water quality and physico-chemical conditions from 2009 to 2019, the impacts of distinct changes in managed flow, drought, El Niño-related increases in precipitation, and intensive storms and hurricanes are explored with respect to changes in water quality and resulting ecosystem effects, with a focus on understanding why picocyanobacterial blooms formed when they did. Drought produced hyper-salinity conditions that were associated with a seagrass die-off. Years later, increases in precipitation resulting from intensive storms and a hurricane were associated with high loads of organic nutrients, and declines in pH, likely due to high organic acid input and decaying organic matter, collectively leading to physiologically favorable conditions for growth of the picocyanobacterium, Synechococcus spp. These conditions, including very high concentrations of NH4+, were likely inhibiting for seagrass recovery and for growth of competing phytoplankton or their grazers. Given projected future climate conditions, and anticipated cycles of drought and intensive storms, the likelihood of future seagrass die-offs and picocyanobacterial blooms is high.