Increased loadings of nitrogen (N) from fertilizers, top soil, sewage, and atmospheric deposition are important drivers of eutrophication in coastal waters globally. Monitoring seawater and macroalgae can reveal long-term changes in N and phosphorus (P) availability and N:P stoichiometry that are critical to understanding the global crisis of coral reef decline. Analysis of a unique 3-decade data set for Looe Key reef, located offshore the lower Florida Keys, showed increased dissolved inorganic nitrogen (DIN), chlorophyll a, DIN:soluble reactive phosphorus (SRP) ratios, as well as higher tissue C:P and N:P ratios in macroalgae during the early 1990s. These data, combined with remote sensing and nutrient monitoring between the Everglades and Looe Key, indicated that the significant DIN enrichment between 1991 and 1995 at Looe Key coincided with increased Everglades runoff, which drains agricultural and urban areas extending north to Orlando, Florida. This resulted in increased P limitation of reef primary producers that can cause metabolic stress in stony corals. Outbreaks of stony coral disease, bleaching, and mortality between 1995 and 2000 followed DIN enrichment, algal blooms, and increased DIN:SRP ratios, suggesting that eutrophication interacted with other factors causing coral reef decline at Looe Key. Although water temperatures at Looe Key exceeded the 30.5 °C bleaching threshold repeatedly over the 3-decade study, the three mass bleaching events occurred only when DIN:SRP ratios increased following heavy rainfall and increased Everglades runoff. These results suggest that Everglades discharges, in conjunction with local nutrient sources, contributed to DIN enrichment, eutrophication, and increased N:P ratios at Looe Key, exacerbating P limitation, coral stress and decline. Improved management of water quality at the local and regional levels could moderate N inputs and maintain more balanced N:P stoichiometry, thereby reducing the risk of coral bleaching, disease, and mortality under the current level of temperature stress.