The continental shelf of the northern Gulf of Mexico receives high dissolved inorganic nitrogen and phosphorus loads from the Mississippi and Atchafalaya rivers. The nutrient load results in high primary production in the river plumes and contributes to the development of hypoxia on the Louisiana shelf in summer. While phytoplankton growth is considered to be typically nitrogen-limited in marine waters, phosphorus limitation has been observed in this region during periods of peak river discharge in spring and early summer. Here we investigate the presence, spatio-temporal distribution and implications of phosphorus limitation in the plume region using a circulation model of the northern Gulf of Mexico coupled to a multi-nutrient ecosystem model. Results from a 7-yr simulation (2001–2007) compare well with several sources of observations and suggest that phosphorus limitation develops every year between the Mississippi and Atchafalaya deltas. Model simulations show that phosphorus limitation results in a delay and westward shift of a fraction of river-stimulated primary production. The consequence is a reduced flux of particulate organic matter to the sediment near the Mississippi delta, but slightly enhanced fluxes west of Atchafalaya Bay. Simulations with altered river phosphate concentrations (±50%) show that significant variation in the spatial extent of phosphorus limitation (±40% in July) results from changes in phosphate load.