Dark spot disease (DSD) was first reported within Florida’s coral reefs in the 1990s but factors affecting its spatial distribution have not been well studied. We used a 14-year (2005–2019) coral monitoring data set, utilizing 2242 surveys collected along Florida’s coral reefs (about 530 linear km) to explore the spatial and temporal patterns of DSD occurrence. We built predictive statistical models to test for correlations between a suite of environmental and human impact factors and the occurrence of DSD in the reef coral, Siderastrea siderea. DSD in S. siderea is a chronic disease which occurred in all 14 years of the study. Annual DSD prevalence ranged from 0.45% to 4.4% and the proportion of survey sites that had DSD ranged from 4.8% to 30.9%. During the study period, DSD became more widespread across Florida’s coral reefs and affected a higher proportion of S. siderea populations. Spatial variations in DSD correlated with environmental and human factors which together explained 64.4% of the underlying variability. The most influential factors were concentration of silica in the surface waters (a proxy for freshwater input), the total number of coral hosts, and distance to septic areas. DSD occurred in all regions, but the highest cumulative prevalence occurred in the upper Keys on reefs around major urban centers with links to coastal water discharges. Our results support the hypothesis that coastal water quality is a key component of DSD disease dynamics in Florida and provides motivation for addressing land–sea connections to ameliorate disease occurrence in the region.