Transient ecosystem-level disturbances such as oxygen depletion (hypoxia) in aquatic systems modulate species distributions and interactions. In highly eutrophic systems, hypoxic areas (“dead zones”) have expanded around the world, temporarily preventing many demersal predators from accessing their food resources. Here, we investigate how yellow perch (Perca flavescens), an exploited, cool-water mesopredator, interact with their dominant invertebrate prey in benthic habitat–non-biting midge (chironomid) larvae–as bottom-water hypoxia develops in central Lake Erie (United States–Canada) during summer. We apply linear mixed-effects models to individual-level data from basin-wide field surveys on size-based interactions between perch and midge larvae under varying habitat conditions and resource attributes. We test if 1) midge populations (larval body size and density) differ among habitat states (unstratified normoxia, stratified normoxia, and stratified hypoxia); and 2) size-based perch–midge interactions (predator–prey mass ratio or PPMR) differ among habitat states with varying temperature and midge density. Midge populations remained highly abundant after bottom-water oxygen depletion. Despite their high densities, midge larvae also maintained their body size in hypoxic water. In contrast, perch on average consumed relatively smaller (by up to ~64%) midges (higher PPMR) in warmer and hypoxic water, while prey size ingested by perch shrunk less in areas with higher midge density. Our analysis shows that hypoxia-tolerant midges largely allow perch to maintain their consumer–resource relationships in contracted habitats through modified size-mediated interactions in dead zones during summer, revealing plasticity of their trophic coupling in the chronically perturbed ecosystem.