We provide a case study prioritizing instream flow restoration activities by sub-basin according to the habitat needs of Endangered Species Act (ESA)-listed salmonids relative to climate change in the central Columbia River basin in Washington State (USA). The objective is to employ scenario analysis to inform and improve existing instream flow restoration projects. We assess the sensitivity of late summer (July, August, and September) flows to the following scenario simulations – singly or in combination: climate change, changes in the quantity of water used for irrigation and possible changes to existing water resource policy. Flows for four sub-basins were modeled using the Water Evaluation and Planning system (WEAP) under historical and projected conditions of 2020 and 2040 for each scenario. Results indicate that Yakima will be the most flow-limited sub-basin with average reductions in streamflow of 41% under climate conditions of 2020 and 56% under 2040 conditions; 1.3–2.5 times greater than those of other sub-basins. In addition, irrigation plays a key role in the hydrology of the Yakima sub-basin – with flow reductions ranging from 78% to 90% under severe to extreme (i.e., 20–40%) increases in agricultural water use (2.0–4.4 times the reductions in the other sub-basins). The Yakima and Okanogan sub-basins are the most responsive to simulations of flow-bolstering policy change (providing salmon with first priority water allocation and at biologically relevant flows), as demonstrated by 91–100% target flows attained. The Wenatchee and Methow sub-basins do not exhibit similar responsiveness to simulated policy changes. Considering climate change only, we conclude that flow restoration should be prioritized first in the Yakima and Wenatchee sub-basins, and second in the Okanogan and Methow. Considering both climate change and possible policy changes, we recommend that the Yakima sub-basin receive the highest priority for flow restoration activities to sustain critical instream habitat for ESA-listed salmonids.