High-resolution numerical simulations of the northern Gulf of Mexico region using the Hybrid Coordinate Ocean Model (HYCOM) were employed to investigate the dynamical processes controlling the fate of the Mississippi River plume, in particular the conditions that favor cross-marginal transport. The study focuses on the effects of topography, wind-driven and eddy-driven circulation on the offshore removal of plume waters. A realistically forced simulation (nested in a data-assimilative regional Gulf of Mexico HYCOM model) reveals that the offshore removal is a frequent plume pathway. Eastward wind-driven currents promote large freshwater transport toward the shelf break and the DeSoto Canyon, where eddies with diameters ranging from 50 to 130 km interact with the buoyant plume and effectively entrain the riverine waters. Our estimates show that the offshore removal by eddies can be as large as the wind-driven shelf transport. The proximity of eddies to the shelf break is a sufficient condition for offshore removal, and shelf-to-offshore interaction is facilitated by the steep bottom topography near the delta. Strong eddy-plume interactions were observed when the Loop Current System impinged against the shelf break, causing the formation of coherent, narrow low-salinity bands that extended toward the gulf interior. The offshore pathways depend on the position of the eddies near the shelf edge, their life span and the formation of eddy pairs that generate coherent cross-shelf flows. This study elucidates the dynamics that initiate a unique cross-marginal removal mechanism of riverine low-salinity, nutrient-rich waters, allowing their export along connectivity pathways, induced by a large-scale current system.