Increasing global CO₂ and local land use changes coupled with increased nutrient pollution are threatening estuaries worldwide. Local changes of estuarine chemistry have been documented, but regional associations and trends comparing multiple estuaries latitudinally have not been evaluated. Rapid climate change has impacted the annual and decadal chemical trends in estuaries, with local ecosystem processes enhancing or mitigating the responses. Here, we compare pH, dissolved oxygen, temperature, and salinity data from 10 Florida shellfish estuaries and hundreds of shellfish bed stations. Over 80,000 measurements, spanning from 1980 to 2008, taken on Atlantic Ocean and West Florida coast showed significant regional trends of consistent pH decreases in 8 out of the 10 estuaries, with an average rate of decrease on the Gulf of Mexico side estuaries of Florida of 7.3 × 10⁻⁴ pH units year⁻¹, and average decrease on the Atlantic Coast estuaries of 5.0 × 10⁻⁴ pH units year⁻¹. The rates are approximately 2–3.4 times slower than observed in pH decreases associated with ocean acidification in the Atlantic and Pacific. Other significant trends observed include decreasing dissolved oxygen in 9 out of the 10 estuaries, increasing salinity in 6 out of the 10, and temperature increases in 3 out of the 10 estuaries. The data provide a synoptic regional view of Florida estuary trends which reflect the complexity of changing climate and coastal ocean acidification superimposed on local conditions. These data provide context for understanding, and interpreting the past and predicting future of regional water quality health of shellfish and other organisms of commercial and ecological significance along Florida’s coasts.