Major fisheries and aquatic habitat restoration efforts are stymied in coastal waters, such as the Long Island Sound, the Potomac and Gulf of Mexico, due to upstream land use impacts causing nutrient amplification, algal blooms and depleted oxygen in both local waters and many miles downstream. Hypoxia can exacerbate stress on commercial species, degrade habitat, shift ecological communities and destroy fisheries-dependent cultures and economies. Individual estuaries and species may differ in their response to eutrophication and hypoxic conditions. Fisheries biologists must understand and communicate these water quality impacts with other sectors that make decisions regarding working lands that cause habitat impairments. Similarly, fisheries allies may exist among sectors that also rely on high quality source water for drinking, industry, and recreation. For example, according to water quality models, Midwestern states within the upper Mississippi River watershed currently contribute the greatest nutrient load to the Gulf of Mexico hypoxic zone. Recent extensive new tile drainage and reversion of Conservation Reserve Program lands to row crops in the Dakotas and Minnesota, as well as increased irrigation in central and southwestern portions of the basin, may dramatically reduce fish and wildlife habitat across the Mississippi Basin and substantially increase nutrient loading to the Gulf. Properly positioned, upland and riparian wildlife conservation actions can also filter nutrients in addition to providing habitat. Conversely, water quality improvement practices can benefit fisheries and aquatic habitat. In the future, landscape scale challenges such as climate change and socioeconomic conditions will continue to drive both the causes and consequences of hypoxia. To reduce local and downstream water quality impacts to fisheries and aquatic resources, the conservation community must have relatable predictive models, optimization tools, and evaluation metrics to prioritize and adaptively manage the design and configuration of conservation actions that detect and alleviate hypoxic impacts.