Marine and terrestrial studies show that small, sedentary herbivores that utilize plants as both food and habitat can gain enemy-free space by living on hosts that are chemically defended from larger, generalist consumers. Although large herbivores are increasingly recognized as important consumers of macrophytes in freshwater communities, the potential indirect effects of herbivory on plant-associated macroinvertebrates have rarely been studied. Here, we show that the large, generalist consumers in a riverine system, Canada geese, Branta canadensis, and crayfish, Procambarus spiculifer, both selectively consumed riverweed, Podostemum ceratophyllum, over an aquatic moss, Fontinalis novae-angliae, even though moss comprised 89% of the total plant biomass on riverine rocky shoals. Moss supported twice as many plant-associated macroinvertebrates as riverweed, suggesting that it might provide a spatial refuge from consumption by these larger consumers. Bioassay-guided fractionation of moss extracts led to the isolation of a C18 acetylenic acid, octadeca-9,12-dien-6-ynoic acid, that deterred crayfish feeding. In contrast to results with Canada geese and crayfish, both the amphipod Crangonyx gracilis and the isopod Asellus aquaticus consumed significant amounts of moss but rejected riverweed in laboratory feeding assays. Moreover, neither amphipod nor isopod feeding was deterred by the crude organic extract of Fontinalis, suggesting that these mesograzers tolerate or circumvent the chemical defenses that deterred larger consumers. Thus, herbivory by large, generalist herbivores may drive freshwater plant community structure towards chemically defended plants and favor the ecological specialization of smaller, less mobile herbivores on unpalatable hosts that represent enemy-free space.