A large region of low-dissolved-oxygen bottom waters (hypoxia) forms nearly every summer in the northern Gulf of Mexico because of nutrient inputs from the Mississippi River Basin and water column stratification. Policymakers developed goals to reduce the area of hypoxic extent because of its ecological, economic, and commercial fisheries impacts. However, the goals remain elusive after 30 y of research and monitoring and 15 y of goal-setting and assessment because there has been little change in river nitrogen concentrations. An intergovernmental Task Force recently extended to 2035 the deadline for achieving the goal of a 5,000-km2 5-y average hypoxic zone and set an interim load target of a 20% reduction of the spring nitrogen loading from the Mississippi River by 2025 as part of their adaptive management process. The Task Force has asked modelers to reassess the loading reduction required to achieve the 2035 goal and to determine the effect of the 20% interim load reduction. Here, we address both questions using a probabilistic ensemble of four substantially different hypoxia models. Our results indicate that, under typical weather conditions, a 59% reduction in Mississippi River nitrogen load is required to reduce hypoxic area to 5,000 km2. The interim goal of a 20% load reduction is expected to produce an 18% reduction in hypoxic area over the long term. However, due to substantial interannual variability, a 25% load reduction is required before there is 95% certainty of observing any hypoxic area reduction between consecutive 5-y assessment periods.