Watershed assessments have become common for prioritizing restoration in river networks. These assessments primarily focus on geomorphic conditions of rivers but less frequently incorporate non-geomorphic abiotic factors such as water chemistry and temperature, and biotic factors such as the structure of food webs. Using a dynamic food web model that integrates physical and ecological environmental conditions of rivers, we simulated how juvenile salmon (Oncorhynchus spp.) biomass responded to restoration at twelve sites distributed across the Methow River (Washington, USA), ranging from headwater tributaries to mainstem reaches. We explored responses to three common river restoration strategies: (1) physical habitat modification, (2) nutrient supplementation, and (3) increased riparian vegetation cover. We also simulated how different food web configurations that exist in salmon-bearing streams, such as the presence of ‘non-target’ fishes and ‘armored’ predation resistant invertebrates, could mediate restoration outcomes. Some locations in the river network experienced relatively large increases in modeled fish biomass with restoration, whereas other locations were almost entirely unresponsive. Spatial variation in restoration outcomes was primarily controlled by non-geomorphic environmental conditions, such as nutrient availability, water temperature, and stream canopy cover. Restoration responses also varied significantly with different food web configurations, suggesting that as the structure of food webs varies across river networks, so too could the outcome of restoration. These findings illustrate that ecological responses to restoration may exhibit substantial spatial variation within river networks, resulting from heterogeneity in environmental conditions that are commonly overlooked—but which can and should be considered—in restoration planning and prioritization.