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Water column nutrient concentrations and autotrophy in oligotrophic ecosystems are sensitive to eutrophication and other long-term environmental changes and disturbances. Disturbance can be defined as an event or process that changes the structure and response of an ecosystem to other environmental drivers. The role disturbance plays in regulating ecosystem functions is challenging because the effect of the disturbance can vary in magnitude, duration, and extent spatially and temporally. We measured changes in total nitrogen (TN), dissolved inorganic nutrient (DIN), total phosphorus (TP), soluble reactive phosphorus (SRP), total organic carbon (TOC), and chlorophyll-a (Chl-a) concentrations throughout the Everglades, Florida Bay, and the Florida Keys. This region has been subjected to a variety of natural and anthropogenic disturbances including tropical storms, fires, eutrophication, and rapid increases in water levels from sea-level rise and freshwater restoration. We hypothesized that the rate of change in water quality would be greatest in the coastal ecotone where disturbance frequencies and marine P concentrations are highest, and in freshwater marshes closest to hydrologic changes from restoration. We applied trend analyses on multi-decadal data (1996–2019) collected from 461 locations distributed from inland freshwater Everglades (ridge and slough) to outer marine reefs along the Florida Keys, USA. Total Organic Carbon decreased throughout the study area and was the only parameter with a systematic trend throughout the study area. All other parameters had spatially heterogeneous patterns in long-term trends. Results indicate more variability across a large spatial and temporal extent associated with changes in biogeochemical indicators and water quality conditions. Chemical and biological changes in oligotrophic ecosystems are important indicators of environmental change, and our regional ridge-to-reef assessment revealed ecosystem-specific responses to both long-term environmental changes and disturbance legacies.