The subaqueous delta of the Mississippi River, the largest river system in the conterminous U.S., has entered a stage of retrogradation caused by multiple natural and anthropogenic activities. Since the 1950s, the suspended sediment load of the Mississippi River has decreased by ~50% due primarily to the construction of >50,000 dams in the Mississippi basin. The impact of this decreased sediment load has been observed in subaerial environments, but the impact on sedimentation and geomorphology of the subaqueous delta front has yet to be examined. To identify historic trends in sedimentation patterns, we compiled bathymetric datasets, including historical charts, industry and academic surveys, and National Oceanic and Atmospheric Administration hydrographic data, collected between 1764 and 2009. The progradation rate (measured at the 10 m depth contour) of Southwest Pass, which receives 69% of the suspended sediment load reaching Head of Passes, has decreased from ~67 m/yr between 1874 and 1940 to ~26 m/yr between 1940 and 1979, with evidence of further deceleration from 1979 to 2009. At South Pass and Pass a Loutre, the delta front has entered the destructive phase, with the 10 m contour retreating at rates >20 m/yr at both passes since 1979. Advancement of the delta front also decelerated in deeper water (in some areas out to ~180 m depth). Except locally, where mudflow lobes are advancing, deeper contours show a pattern of decreasing progradation rate between 1874–1940 and 1979–2005 time periods. Furthermore, based on differences measured between available bathymetric datasets, the sediment accumulation rate across the delta front decreased by ~73% for the same period. The retention rate of Mississippi River sediment on the delta front ranged from 67 to 81% for the time periods assessed, with total sediment load stored on the delta front equal to 317 ± 54 Mt/yr from 1874 to 1940, 145 ± 25 Mt/yr from 1940 to 1979, and 87 ± 15 Mt/yr from 1979 to 2005. We document for the first time that the Mississippi River delta front has entered a phase of retrogradation, which will likely be accelerated by future upstream activities that divert a portion of the sediment load to the upper delta for coastal protection and restoration projects. The decline of the subaqueous Mississippi River Delta has critical implications for biogeochemical cycling, subaqueous mass wasting, and sediment dispersal to the coastal ocean.