The invasive Asian golden mussel Limnoperna fortunei is continuously expanding through South America, altering aquatic ecosystem structure and functioning. While several native fish species predate on this mussel, these interactions, and their consequences for the food web, have not been studied in depth. We combine a survey of the fish assemblage trophic structure using gut contents and stable isotope analysis with an in situ exclusion experiment in order to: (a) determine the main fish species predating on L. fortunei; (b) estimate the contribution of L. fortunei to the biomass of fish assemblage; and (c) evaluate the role of fish on the density and maximum shell length of L. fortunei in the lower Uruguay River (the Río de La Plata Basin). We found that about one third of fish species in the assemblage (28 out of 81 species) consumed L. fortunei, which was an important food item (>10% of the dietary volume and >30% of frequency of occurrence) for 11 fish species. Stable isotope mixing models consistently suggested that >14% of the total biomass of the fish assemblage was derived directly from carbon derived from L. fortunei tissues. In addition, the exclusion experiment demonstrated that fish predation reduces the mussel density by c. 70% and the mussel maximum shell length by c. 40%. Synthesis and applications. Our research suggests a top-down effect of fish on the invasive Asian golden mussel's abundance. This work highlights the need to preserve the native fish communities, particularly in South America, where many vulnerable migratory fish are of key relevance as Limnoperna fortunei consumers. In the light of these findings, actions such as implementing efficient fish passage technologies in the actual (and projected) dams of the Uruguay River basin and elsewhere become essential to avoid local extinctions of these natural invasion controls upstream of the dams.