In August 2014, in situ measurements revealed an intense salinity drop impacting South Florida coral reefs, between Pulley Ridge (Southwest Florida Shelf) and the Florida Keys. The low salinity waters had a surface signal of 32 (down from 35.2) and extended over a 15–20-m deep lens. Satellite observations showed that this abrupt drop in salinity was due to a southeastward export of Mississippi River waters from the Northern Gulf of Mexico (GoM), revealing strong interaction between coastal and oceanic flows. Unlike previous events of marked long-distance Mississippi water export, this episode is not associated with Mississippi flooding conditions, which makes it a unique study case. We have developed a high-resolution (~2 km) comprehensive hydrodynamic numerical model of the GoM to study the conditions that controlled the 2014 Mississippi River water export episode. It is based on the Hybrid Coordinate Ocean Model (HYCOM) and assimilates remotely sensed altimetry and sea surface temperature observations, to ensure that the simulated upper-ocean is realistic. This regional model has a detailed representation of coastal physics (especially river plume dynamics) and employs high-frequency river discharge and atmospheric forcing. The combined use of the simulation and observations reveals a unique pathway that brought Mississippi waters first eastward along the Northern GoM continental shelf, under prevailing winds and the presence of an anticyclonic Loop Current eddy, then southward along the edge of the West Florida Shelf, before reaching the deep GoM. Unlike usually observed, the offshore advection of Mississippi River waters thus took place far from the Delta area, which is another specificity of the 2014 episode. Finally, in the Florida Straits, Mississippi waters were advected from the deep ocean to the continental shelf under the influence of both deep sea (particularly a cyclonic Loop Current frontal eddy) and shelf flows (wind-induced Ekman transport). The simulation, in tandem with data, thus helped analyze processes that are likely to affect the connectivity between reefs in the southern Florida region (Florida Keys, Dry Tortugas, Pulley Ridge) and remote areas (Mississippi Delta), as well as the local connectivity between neighboring reefs.