The ecological features of invasive alien species are crucial for their effective management. However, they are often lacking in newly invaded ecosystems. This is the case of the European catfish Silurus glanis L. in Lake Maggiore, where the species is present since 1990, but no scientific information is available on its ecology. To start filling this knowledge gap, 236 catfish (67 cm to 150 cm of total length) were collected, measured, and dissected for stomach content analyses from three localities and in two habitats (littoral vs. pelagic) in late autumn/early winter. The NPUE and BPUE (individuals (N) and biomass (B, in grams) per unit effort (m2), respectively) of catfish were generally higher in littoral (NPUE > 0.01; BPUE > 96) than in pelagic habitats (NPUE < 0.009; BPUE < 114), but the catfish had, on average, larger sizes in pelagic habitats. Overall, 581 individual prey items were recorded, belonging to 12 taxa. Pelagic catfish specialized their diet exclusively on three prey fish (coregonids, shad, and roach), whilst the diet of littoral catfish was more variable and dominated by crayfish, perch, and roach. These results highlighted for the first time the interaction of larger catfish with the lake’s pelagic food web, and thus possible consequences are discussed, including the potential contrasting role S. glanis may have for the lake’s fishery.