We examined a suite of paleoindicators in 210Pb-dated sediment cores to determine the historical course of primary production, eutrophication, and oxygen stress in the coastal ocean adjacent to the plumes of the Mississippi and Atchafalaya rivers. The assumption that hypoxia is a natural feature of the coastal ecosystem in the northern Gulf of Mexico influenced by the discharge of the Mississippi River system is not supported by paleoindicators in accumulated sediments. There is a propensity for the ecosystem to develop hypoxia because of the high discharge of the Mississippi River and physical dynamics on the continental shelf that support stratification. However, paleoindicators of eutrophication and oxygen conditions record recent anthropogenic influences. The evidence for increased carbon production and accumulation comes from diatoms and their remnants, marine-origin carbon in the sediments, and phytoplankton pigments. Surrogates for oxygen condition, including mineral, isotopic, microfossil, and phytoplankton pigment indicators, indicate worsening oxygen stress. The changes are more apparent in areas of present chronic hypoxia and are coincident with the increasing nitrogen loads from the Mississippi River system beginning in the 1950s. Longer-term shifts in offshore ecology parallel landscape changes within the watershed in the last two centuries. The temporal shifts in this coastal ecosystem parallel the time sequence of similarly eutrophied coastal waters globally and coincide nicely with sediment analyses from other locations.