ABSTRACTGlobally, freshwater ecosystems are threatened by multiple stressors, yet our knowledge of how they interact to affect food web structure remains scant. To address this knowledge gap, we conducted a large‐scale mesocosm experiment to quantify the single and combined effects of three common anthropogenic stressors: warming, increased nutrient loading, and insecticide pollution, on the network structure of shallow lake food webs. We identified both antagonistic and synergistic interactive effects depending on whether the stressors affected negative or positive feedback loops, respectively. Overall, multiple stressors simplified the food web, elongated energy transfer pathways, and shifted biomass distribution from benthic to more pelagic pathways. This increased the risk of a regime shift from a clear‐water state dominated by submerged macrophytes to a turbid state dominated by phytoplankton. Our novel results highlight how multiple anthropogenic stressors can interactively disrupt food webs, with implications for understanding and managing aquatic ecosystems in a changing world.