Decreased salinity and submarine light associated with hurricanes of 2004–2005 impacted seagrass habitats in the Florida coastal zone. A combination of salinities ≤20 and light attenuation ≥1.5 m−1 resulting from the freshwater discharge in 2005 were among the drivers for a widespread decrease in the coverage and biomass of Syringodium filiforme (manatee grass) in 2006. These observations provided an opportunity to develop and apply a modeling framework to simulate responses of S. filiforme to variable water quality. The framework connects water column variables to field monitoring of seagrass abundance and salinity growth response experiments. The base model was calibrated with macrophyte abundance observed in southern Indian River Lagoon (IRL) from 2002 to 2007 and tested against shoot data from a different time (1997–2002) and nearby location in the IRL. Model shoot biomass (gC m−2) was similar to field observations (r2 = 0.70) while responding to monthly seasonal fluctuations in salinity and light throughout the 6-year simulations. Field and model results indicated that S. filiforme growth and survival were sensitive to, and increased with, rising salinity throughout 2007. This modeling study emphasizes that discharge, salinity, and submarine light are inter-dependent variables affecting South Florida seagrass habitats on seasonal to inter-annual time scales.